Oxetanone derivatives

ABSTRACT

This invention relates to novel oxetanone derivative compounds and processes for producing such derivatives that are useful as lipase inhibitors. Further the invention relates to processes for producing salts and for producing pharmaceutical compositions compounds comprising at least one such oxetanone derivative or salt, as well as methods for using such compounds and compositions for inhibiting lipases.

The present application is a continuation-in-part of Ser. No. 09/698,307Oct. 27, 2000, which is a continuation-in-part of Ser. No. 09/618,328,filed Jul. 18, 2000, abandoned which is a continuation-in-part of Ser.No. 09/431,551 filed Oct. 29, 1999, now U.S. Pat. No. 6,235,305 which isa continuation-in-part of Ser. No. 60/165,960, filed Nov. 17, 1999.

FIELD OF THE INVENTION

This invention relates to novel oxetanone derivative compounds andprocesses for producing such derivatives which are useful as lipaseinhibitors. Further the invention relates to processes for producingsalts and for producing pharmaceutical compositions compounds comprisingat least one such oxetanone derivative or salt, as well as methods forusing such compounds and compositions for inhibiting lipases. In oneaspect the invention relates to lipase inhibitors which include on thesame molecule an oxetanone derivative portion capable of inhibiting alipase and a non-absorbable moiety such a polysaccharide, which arecovalently linked or are in the form of a salt. In a preferred aspect ofthe invention the non-absorbable moiety is lipophilic and will associatewith oils or fats. An absorbable oxetanone lipase inhibitor may berendered non-absorbable by covalent linking it directly or indirectly toa non-absorbable moiety and thereby producing a novel non-absorbablelipase inhibitor.

BACKGROUND OF THE INVENTION

Some lipase-inhibiting oxetanones and intermediates for making them arewell known. See for example, U.S. Pat. Nos. 5,931,463, 4,189,438 and4,202,824. However, there is a need for improved oxetanones that arehave low toxicity and are essentially not absorbable by the digestivesystem of mammals such as dogs, cats, non-human primates and humanprimates.

Lipase inhibitors such as esterastin (see U.S. Pat. No. 4,189,438),tetrahydroesterastin (3,5-hydroxy-2hexadeca-7,10-dienoic 1,3-lactone),3,5-dihydroxy-2-hexylhexadeca-7,10-dienoic 1,3-lactone,3,5-di-hydroxy-2-hexylhexadecanoic 1,3-lactone, and the like, arewell-known as lipase inhibitors and as pancreatic cholesterol esteraseinhibitors. However, such lipase inhibitors are, inter alia, alsosubstantially orally active as immunosuppressants (see U.S. Pat. No.4,189,438 and U.S. Pat. No. 4,202,824), which can be a highly undesiredside activity in a normal or immunosuppressed person. Such lipaseinhibitor compounds are 3,5 dihydroxy 1,3 lactone derivative compounds,wherein the 5-hydroxyl group may be esterified at the 5 position or ishydrolyzed to the free hydroxyl group.

A popular lipase inhibiting compound which is substantiallynon-absorbable is known as Orlistat((2S,3S,5S)-5-[(S)-2-formamido-4-methyl-valeryloxy]-2-hexyl-3-hydroxy-hexadecanoic1,3 acid lactone, see U.S. Pat. No. 5,643,874). This compound is asteric isomer derivative of tetrahydroesteratin and its 5-hydroxyl groupis esterified with a [S-2-formamido-4-methyl-valeryloxy] group. Orlistathas been used to inhibit lipases in the body and thereby prevent theabsorption of dietary fat. At a 120 mg dose of Orlistat, taken beforeconsuming a fat-containing meal (or up to one hour after eating such ameal), up to one-third of the fat eaten at a given meal will not beabsorbed by the average person and utilized as dietary fat calories. Theundigested fat passes directly through the digestive system as an oiland is eliminated from the bowel in its oily undigested form.

Certain polysaccharides are non-absorbable and some polysaccharides havethe side benefit of reducing lipid absorption by the body. Defatted ricegerm polysaccharides and sulfated polysaccharides are also lipaseinhibitors, which are high molecular weight compounds that do not appearto have any lactone moieties and seem to work by a different mechanism,binding the lipase and removing it from the digestive system when theyare discharged from the digestive system. The super fiber Chitosan,which is a deacylated polysaccharide derived from shellfish chitan, hasan ability to absorb fat and cholesterol, particularly in combinationwith vitamin C. Chitosan compositions may actually absorb up to 6 to 8times their weight in fat and oils. While the polysaccharide fromshellfish is similar to crude cellulose plant fiber, it has the abilityto significantly bind fat in the digestive system as compared to plantfiber. Further, since polysaccharides, including those which do notpreferentially bind oils over water, are not absorbed by the digestivesystems of animals such as humans, non-human primates, dogs and cats,there is no caloric value to such polysaccharides and they pass throughthe such digestive systems unabsorbed and substantially intact. Examplesof non-absorbable polysaccharides are polysaccharides having a molecularweight of greater than 8 kDa such as dextrans, molecularmicrocrystalline cellulose, wheat bran, oat bran, defatted rice germ,alginic acid, pectin, amylopectin, chitin, crude cellulose, argar,chitosan and the like.

There is a need in the art for non-absorbable lipase inhibitors, as wellas for improved antiadiposity compositions and methods which do notrequire an absolute low-fat diet in order to lower the absorption ofdietary fat as calories.

SUMMARY OF THE INVENTION

In one aspect the present invention relates to novel derivatives oflipase inhibitors which are non-absorbable compounds comprising at leastone lipase inhibitor moiety and at least one non-absorbable polymericmoiety in the same molecule or salt. The lipase inhibitor moiety ispreferably present in the non-absorbable compound in a weight ratio offrom about 1:10 to about 1:60 with respect to the weight of thepolymeric moiety, preferably from about 1:20 to about 1:40, and morepreferably from about 1:25 to 1:35. In one aspect, such lipaseinhibitors comprise at least one lipase inhibitor moiety (or moieties)linked directly or indirectly to such a polymeric moiety. The inventionalso includes pharmaceutical compositions comprising an effective amountof such lipase inhibitors in combination with a pharmaceuticallyacceptable carrier or diluent, which compositions may further comprisean effective amount of a lipophilic, non-absorbable biocompatible,pharmaceutically acceptable oil absorbing polymer.

In another aspect the present invention relates to novel salts ofnon-absorbable lipase inhibitors and a non-absorbable biocompatible,pharmaceutically acceptable oil absorbing polymer. The invention alsoincludes pharmaceutical compositions comprising an effective amount ofsuch lipase inhibitors in combination with a pharmaceutically acceptablecarrier or diluent, which compositions may further comprise an effectiveamount of a lipophilic, non-absorbable biocompatible, pharmaceuticallyacceptable oil absorbing polymer.

In a preferred aspect the present invention relates to novelnon-absorbable derivatives of a 1,3 oxetanone lipase inhibitor, whichinclude at least one 1,3 oxetanone lipase inhibiting moiety that iscovalently or non-covalently linked to a non-absorbable biocompatible,pharmaceutically acceptable polymer moiety to provide a novel lipaseinhibitor compound. Preferred compounds have the dual function ofinhibiting lipases and absorbing fat, in that the non-absorbablebiocompatible, pharmaceutically acceptable polymer moiety of the novellipase inhibitor will bind to fat, carry the bound fat with it throughportions of the digestive system and cause the non-absorbed fat to beeliminated removed from the digestive system as undigested fat. The 1,3oxetanone moiety that is derivatized directly or indirectly with thepolymer moiety according to the invention may be initially an absorbableor non-absorbable moiety and is derivatized by directly or indirectlylinking it to the polymer moiety to form a novel non-absorbable lipaseinhibitor, preferably at the 5 hydroxyl position of a 1,3 oxetanonemoiety.

In a preferred aspect the invention provides compounds having eithernon-covalent linkages of such two moieties or covalent linkages that arehydrolyzed or digested in the digestive system, providing that thelipase inhibiting 1,3 oxetanone derivative moiety that is released inthe digestive system is substantially non-absorbable.

In another preferred aspect the invention provides compounds havingeither a non-covalent linkage of such two moieties or a covalent linkagethat is not hydrolyzed or digested in the digestive system, whereby thelipase inhibiting 1,3 oxetanone derivative moiety remains linked to thepolymer moiety via such non-covalent or covalent linkage and is notreleased in the digestive system.

In one aspect of the invention, an absorbable lipases such as esterastinmoiety, tetrahydroestrastin, or a similar moiety, is renderednon-absorbable by coupling it directly or indirectly to a non-absorbablebiocompatible, pharmaceutically acceptable polymer moiety, such as apolysaccharide, to render the lipase essentially non-absorbable by thedigestive system of an animal such as a dog, cat, non-human primate orhumans. Preferred lipase inhibitor moieties that are coupled to thepolysaccharide include at least one lipase inhibitor which is a memberselected from the group consisting of esterastin, tetrahydro-esterastin(3,5-hydroxy-2-hexadeca-7, 10-dienoic 1,3-lactone),3,5-dihydroxy-2-hexylhexadeca-7,10-dienoic 1,3-lactone,3,5-di-hydroxy-2-hexylhexadecanoic 1,3-lactone, and the like.Preferably, such lipase inhibitor is coupled to a non-absorbablebiocompatible, pharmaceutically acceptable polymer moiety, such as apolysaccharide, to render the lipase non-absorbable by the digestivesystem of an animal such as a dog, cat, non-human primate or humans.Particularly preferred polysaccharides have at least one member selectedfrom the group consisting of dextrans, molecular microcrystallinecellulose, wheat bran, oat bran, defatted rice germ, alginic acid,pectin, amylopectin, chitin, crude cellulose, argar, chitosan, achitosan methylbenzoic acid ester ether derivative, and the like.Particularly preferred bound lipase inhibitors are lipase inhibitorsbound via a derivatized group on the lipase such as a derivatizednitrogen, acid or alcohol group to a group on the polymer moiety such asa derivatized alcohol, acid or amino group. Preferably, a divalentbridging group is attached at one portion of the bridging group to anamino group on the polysaccharide and attached at a second portion ofthe bridging group to a lipase inhibitor and the moiety. Furtherpreferred are such compounds wherein further amino groups, alcoholgroups or amino groups and alcohol groups on the polysaccharide aremodified to present open organic acyl group sufficient to render thepolysaccharide capable of associating with both organic neutral to acidgroups and polar inorganic groups such as water such that a homogeneousgel can be formed. Also preferred are compounds wherein the lipaseinhibitor is an oxetanone moiety which is derivatized to provide anamino group which is further derivatized to form a carboxamide group,followed by linking the carboxamide group to an acid group, alcoholgroup or amino group on the polymer moiety via a bridging group, whichpolymer moiety may have been derivativized in order to provide such anacid or alcohol group for attachment. Examples of such attachments areillustrated below by a preferred embodiment of the invention.

In another aspect the present invention relates to pharmaceuticalcompositions comprising a lipase inhibiting effective amount of at leastone lipase inhibitor which is coupled to a digestively non-absorbablemoiety. Preferred are such pharmaceutical compositions comprising aneffective amount of a lipases coupled to a non-absorbable biocompatible,pharmaceutically acceptable polymer moiety, such as a polysaccharide,wherein the lipase is essentially non-absorbable by the digestive systemof an animal such as a dog, cat, non-human primate or humans.

In still another aspect, the present invention relates to a method fortreating adiposity or obesity by administering to a patient before afat-contain meal, or up to one hour after such a meal is consumed, anamount of at least one lipase inhibitor which is bound to anon-absorbable polymer moiety in an amount effective to inhibit theabsorption of up to one-third of the dietary fat in such a meal. Inparticular, a preferred method comprises administering at one lipaseinhibitor which is a member selected from the group consisting ofesterastin, tetrahydro-esterastin (3,5-hydroxy-2hexadeca-7,10-dienoic1,3-lactone), 3,5-dihydroxy-2-hexylhexadeca-7, 10-dienoic 1,3-lactone,3,5-di-hydroxy-2-hexylhexadecanoic 1,3-lactone, and the like, whereinsuch lipase inhibitor is coupled to a non-absorbable biocompatible,pharmaceutically acceptable polymer moiety, such as a polysaccharide, torender the lipase non-absorbable by the digestive system of an animalsuch as a dog, cat, non-human primate or humans. Particularly preferredpolysaccharides are at least one member selected from the groupconsisting of dextrans, molecular microcrystalline cellulose, wheatbran, oat bran, defatted rice germ, alginic acid, pectin, amylopectin,chitin, crude cellulose, argar, chitosan and the like. Particularlypreferred bound lipase inhibitors are lipase inhibitors bound via aderivatized nitrogen, acid or alcohol group to a derivatized alcohol,acid or amino group on the polymer moiety.

A divalent bridge terminal amino attachment/terminal ester bridge,between the lipase inhibitor moiety and the polymer moiety which isderived from an alcohol group on the lipase inhibitor moiety and anamino group on the polymer moiety, respectively reacting with a bridginggroup is a preferred coupling of the lipase inhibitor to the moiety.

Another preferred bridge between the lipase inhibitor moiety and thepolymer moiety includes at least amino terminal bridge formed from anamino group on the polymer moiety and at least one carboxamide bondterminal bridge attachment to the lipase inhibitor derivative. Furtherpreferred are compounds wherein at least one amino acid derivative islocated in the bridge, and is bound directly or indirectly to the 5hydroxyl position on the 1,3 oxetanone lipase inhibitor moiety via anester linkage.

The preferred compounds also include their pharmaceutically acceptableisomers, hydrates, solvates, salts and prodrug derivatives.

DETAILED DESCRIPTION OF THE INVENTION

Definitions

In accordance with the present invention and as used herein, thefollowing terms are defined with the following meanings, unlessexplicitly stated otherwise.

The term “alkenyl” refers to a trivalent straight chain or branchedchain unsaturated aliphatic radical. The term “alkinyl” (or “alkynyl”)refers to a straight or branched chain aliphatic radical that includesat least two carbons joined by a triple bond. If no number of carbons isspecified alkenyl and alkinyl each refer to radicals having from 2-12carbon atoms.

The term “alkyl” refers to saturated aliphatic groups includingstraight-chain, branched-chain and cyclic groups having the number ofcarbon atoms specified, or if no number is specified, having up to 12carbon atoms. The term “cycloalkyl” as used herein refers to a mono-,bi-, or tricyclic aliphatic ring having 3 to 14 carbon atoms andpreferably 3 to 7 carbon atoms.

The term “bridging group” refers to a bifunctional chain or spacer groupcapable of reacting with one or more functional groups on a lipaseinhibitor compound and then react with a second same or differentfunctional group on a polymer compound in order to form a linkedstructure or conjugate between the two compounds. The bond formedbetween the bridging group and each of the two moieties is preferably ofa type that is resistant to cleavage by the digestive environment whenthe linked lipase moiety would be absorbable upon cleavage of the bond.In one aspect, the bridging group is of the formula X-R-X, wherein R isa member selected from a straight-chained or branched alkyl group, astraight-chained or branched alkenyl group, a straight-chained orbranched alkynyl group, a mono acyl group, a diacyl group and the like,which R portion of the chain may include a cycloalkyl or an aryl group,and X is a functionally reactive group such as a halogen, or acid group,under special reaction conditions as described hereinafter. Particularlypreferred bridging groups form a ester terminal and amino terminal,ether terminal/acyl terminal bridge that is resistant to cleavage by thedigestive environment. In one aspect bridging groups that are cleaved bythe digestive group to release an essentially non-absorbable lipaseinhibitor are preferred. Examples of alkylene halogen terminal/acylterminal bridging group forming compounds are a C₂ to C₂₀ n-haloalkanoicacid or an ester thereof, such as 6-bromohexanoic acid, 12-bromolauricacid, haloloweralkylbenzoic acid, and the like.

As used herein, the terms “carbocyclic ring structure” and “C₃₋₁₆carbocyclic mono, bicyclic or tricyclic ring structure” or the like areeach intended to mean stable ring structures having only carbon atoms asring atoms wherein the ring structure is a substituted or unsubstitutedmember selected from the group consisting of: a stable monocyclic ringwhich is aromatic ring (“aryl”) having six ring atoms; a stablemonocyclic non-aromatic ring having from 3 to 7 ring atoms in the ring;a stable bicyclic ring structure having a total of from 7 to 12 ringatoms in the two rings wherein the bicyclic ring structure is selectedfrom the group consisting of ring structures in which both of the ringsare aromatic, ring structures in which one of the rings is aromatic andring structures in which both of the rings are non-aromatic; and astable tricyclic ring structure having a total of from 10 to 16 atoms inthe three rings wherein the tricyclic ring structure is selected fromthe group consisting of: ring structures in which three of the rings arearomatic, ring structures in which two of the rings are aromatic andring structures in which three of the rings are non-aromatic. In eachcase, the non-aromatic rings when present in the monocyclic, bicyclic ortricyclic ring structure may independently be saturated, partiallysaturated or fully saturated. Examples of such carbocyclic ringstructures include, but are not limited to, cyclopropyl, cyclobutyl,cyclopentyl, cyclohexyl, adamantyl, cyclooctyl, [3.3.0]bicyclooctane,[4.3.0]bicyclononane, [4.4.0]bicyclodecane (decalin),2.2.2]bicyclooctane, fluorenyl, phenyl, naphthyl, indanyl, adamantyl, ortetrahydronaphthyl (tetralin). Moreover, the ring structures describedherein may be attached to one or more indicated pendant groups via anycarbon atom which results in a stable structure. The term “substituted”as used in conjunction with carbocyclic ring structures means thathydrogen atoms attached to the ring carbon atoms of ring structuresdescribed herein may be substituted by one or more of the substituentsindicated for that structure if such substitution(s) would result in astable compound.

The term “aryl” which is included with the term “carbocyclic ringstructure” refers to an unsubstituted or substituted aromatic ring,substituted with one, two or three substituents selected fromloweralkoxy, loweralkyl, loweralkylamino, hydroxy, halogen, cyano,hydroxyl, mercapto, nitro, thioalkoxy, carboxaldehyde, carboxyl,carboalkoxy and carboxamide, including but not limited to carbocyclicaryl, heterocyclic aryl, and biaryl groups and the like, all of whichmay be optionally substituted. Preferred aryl groups include phenyl,halophenyl, loweralkylphenyl, napthyl, biphenyl, phenanthrenyl andnaphthacenyl.

The term “arylalkyl” which is included with the term “carbocyclic aryl”refers to one, two, or three aryl groups having the number of carbonatoms designated, appended to an alkyl group having the number of carbonatoms designated. Suitable arylalkyl groups include, but are not limitedto, benzyl, picolyl, naphthylmethyl, phenethyl, benzyhydryl, trityl, andthe like, all of which may be optionally substituted.

As used herein, the term “heterocyclic ring” or “heterocyclic ringsystem” is intended to mean a substituted or unsubstituted memberselected from the group consisting of stable monocyclic ring having from5-7 members in the ring itself and having from 1 to 4 hetero ring atomsselected from the group consisting of N, O and S; a stable bicyclic ringstructure having a total of from 7 to 12 atoms in the two rings whereinat least one of the two rings has from 1 to 4 hetero atoms selected fromN, O and S, including bicyclic ring structures wherein any of thedescribed stable monocyclic heterocyclic rings is fused to a hexane orbenzene ring; and a stable tricyclic heterocyclic ring structure havinga total of from 10 to 16 atoms in the three rings wherein at least oneof the three rings has from 1 to 4 hetero atoms selected from the groupconsisting of N, O and S. Any nitrogen and sulfur atoms present in aheterocyclic ring of such a heterocyclic ring structure may be oxidized.Unless indicated otherwise the terms “heterocyclic ring” or“heterocyclic ring system” include aromatic rings, as well asnon-aromatic rings which can be saturated, partially saturated or fullysaturated non-aromatic rings. Also, unless indicated otherwise the term“heterocyclic ring system” includes ring structures wherein all of therings contain at least one hetero atom as well as structures having lessthan all of the rings in the ring structure containing at least onehetero atom, for example bicyclic ring structures wherein one ring is abenzene ring and one of the rings has one or more hetero atoms areincluded within the term “heterocyclic ring systems” as well as bicyclicring structures wherein each of the two rings has at least one heteroatom. Moreover, the ring structures described herein may be attached toone or more indicated pendant groups via any hetero atom or carbon atomwhich results in a stable structure. Further, the term “substituted”means that one or more of the hydrogen atoms on the ring carbon atom(s)or nitrogen atom(s) of the each of the rings in the ring structuresdescribed herein may be replaced by one or more of the indicatedsubstituents if such replacement(s) would result in a stable compound.Nitrogen atoms in a ring structure may be quaternized, but suchcompounds are specifically indicated or are included within the term “apharmaceutically acceptable salt” for a particular compound. When thetotal number of O and S atoms in a single heterocyclic ring is greaterthan 1, it is preferred that such atoms not be adjacent to one another.Preferably, there are no more that 1 O or S ring atoms in the same ringof a given heterocyclic ring structure.

Examples of monocylic and bicyclic heterocylic ring systems, inalphabetical order, are acridinyl, azocinyl, benzimidazolyl,benzofuranyl, benzothiofuranyl, benzothiophenyl, benzoxazolyl,benzthiazolyl, benztriazolyl, benztetrazolyl, benzisoxazolyl,benzisothiazolyl, benzimidazalinyl, carbazolyl, 4aH-carbazolyl,carbolinyl, chromanyl, chromenyl, cinnolinyl, decahydroquinolinyl,2H,6H-1,5,2-dithiazinyl, dihydrofuro[2,3-b]tetrahydrofuran, furanyl,furazanyl, imidazolidinyl, imidazolinyl, imidazolyl, 1H-indazolyl,indolinyl, indolizinyl, indolyl, 3H-indolyl, isobenzofuranyl,isochromanyl, isoindazolyl, isoindolinyl, isoindolyl, isoquinolinyl(benzimidazolyl), isothiazolyl, isoxazolyl, morpholinyl, naphthyridinyl,octahydroisoquinolinyl, oxadiazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,2,5-oxadiazolyl, 1,3,4-oxadiazolyl, oxazolidinyl,oxazolyl, oxazolidinyl, pyrimidinyl, phenanthridinyl, phenanthrolinyl,phenazinyl, phenothiazinyl, phenoxathiinyl, phenoxazinyl, phthalazinyl,piperazinyl, piperidinyl, pteridinyl, purinyl, pyranyl, pyrazinyl,pyroazolidinyl, pyrazolinyl, pyrazolyl, pyridazinyl, pryidooxazole,pyridoimidazole, pyridothiazole, pyridinyl, pyridyl, pyrimidinyl,pyrrolidinyl, pyrrolinyl, 2H-pyrrolyl, pyrrolyl, quinazolinyl,quinolinyl, 4H-quinolizinyl, quinoxalinyl, quinuclidinyl,tetrahydrofuranyl, tetrahydroisoquinolinyl, tetrahydroquinolinyl,6H-1,2,5-thiadazinyl, 1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl,1,2,5-thiadiazolyl, 1,3,4-thiadiazolyl, thianthrenyl, thiazolyl,thienyl, thienothiazolyl, thienooxazolyl, thienoimidazolyl, thiophenyl,triazinyl, 1,2,3-triazolyl, 1,2,4-triazolyl, 1,2,5-triazolyl,1,3,4-triazolyl and xanthenyl. Preferred heterocyclic ring structuresinclude, but are not limited to, pyridinyl, furanyl, thienyl, pyrrolyl,pyrazolyl, pyrrolidinyl, imidazolyl, indolyl, benzimidazolyl,1H-indazolyl, oxazolinyl, or isatinoyl. Also included are fused ring andspiro compounds containing, for example, the above heterocylic ringstructures.

As used herein the term “aromatic heterocyclic ring system” hasessentially the same definition as for the monocyclic and bicyclic ringsystems except that at least one ring of the ring system is an aromaticheterocyclic ring or the bicyclic ring has an aromatic or non-aromaticheterocyclic ring fused to an aromatic carbocyclic ring structure.

The terms “halo” or “halogen” as used herein refer to Cl, Br, F or Isubstituents. The term “haloalkyl”, and the like, refer to an aliphaticcarbon radicals having at least one hydrogen atom replaced by a Cl, Br,F or I atom, including mixtures of different halo atoms. Trihaloalkylincludes trifluoromethyl and the like as preferred radicals, forexample.

The term “methylene” refers to —CH₂—.

The term “pharmaceutically acceptable salts” includes salts of compoundsderived from the combination of a compound and an organic or inorganicacid. These compounds are useful in both free base and salt form. Inpractice, the use of the salt form amounts to use of the base form; bothacid and base addition salts are within the scope of the presentinvention.

“Pharmaceutically acceptable acid addition salt” refers to saltsretaining the biological effectiveness and properties of the free basesand which are not biologically or otherwise undesirable, formed withinorganic acids such as hydrochloric acid, hydrobromic acid, sulfuricacid, nitric acid, phosphoric acid and the like, and organic acids suchas acetic acid, propionic acid, glycolic acid, pyruvic acid, oxalicacid, maleic acid, malonic acid, succinic acid, fumaric acid, tartaricacid, citric acid, benzoic acid, cinnamic acid, mandelic acid,methanesulfonic acid, ethanesulfonic acid, p-toluenesulfonic acid,salicyclic acid and the like.

“Pharmaceutically acceptable base addition salts” include those derivedfrom inorganic bases such as sodium, potassium, lithium, ammonium,calcium, magnesium, iron, zinc, copper, manganese, aluminum salts andthe like. Particularly preferred are the ammonium, potassium, sodium,calcium and magnesium salts. Salts derived from pharmaceuticallyacceptable organic nontoxic bases include salts of primary, secondary,and tertiary amines, substituted amines including naturally occurringsubstituted amines, cyclic amines and basic ion exchange resins, such asisopropylamine, trimethylamine, diethylamine, triethylamine,tripropylamine, ethanolamine, 2-diethylaminoethanol, trimethamine,dicyclohexylamine, lysine, arginine, histidine, caffeine, procaine,hydrabamine, choline, betaine, ethylenediamine, glucosamine,methylglucamine, theobromine, purines, piperizine, piperidine,N-ethylpiperidine, polyamine resins and the like. Particularly preferredorganic nontoxic bases are isopropylamine, diethylamine, ethanolamine,trimethamine, dicyclohexylamine, choline, and caffeine.

“Biological property” for the purposes herein means an in vivo effectoror antigenic function or activity that is directly or indirectlyperformed by a compound of this invention that are often shown by invitro assays. Effector functions include receptor or ligand binding, anyenzyme activity or enzyme modulatory activity, any carrier bindingactivity, any hormonal activity, any activity in promoting or inhibitingadhesion of cells to an extracellular matrix or cell surface molecules,or any structural role. Antigenic functions include possession of anepitope or antigenic site that is capable of reacting with antibodiesraised against it.

In the compounds of this invention, carbon atoms bonded to fournon-identical substituents are asymmetric. Accordingly, the compoundsmay exist as diastereoisomers, enantiomers or mixtures thereof. Thesyntheses described herein may employ racemates, enantiomers ordiastereomers as starting materials or intermediates. Diastereomericproducts resulting from such syntheses may be separated bychromatographic or crystallization methods, or by other methods known inthe art. Likewise, enantiomeric product mixtures may be separated usingthe same techniques or by other methods known in the art. Each of theasymmetric carbon atoms, when present in the compounds of thisinvention, may be in one of two configurations (R or S) and both arewithin the scope of the present invention.

Preferred Embodiments

In one aspect the present invention relates to novel derivatives oflipase inhibitors which are non-absorbable and have a lipase inhibitormoiety and polymeric moiety in the same molecule. The invention alsoincludes pharmaceutical compositions comprising an effective amount ofsuch lipase inhibitors in combination with a pharmaceutically acceptablecarrier or diluent, and may further comprise an effective amount of alipophilic, non-absorbable biocompatible, pharmaceutically acceptableoil absorbing polymer. The lipase inhibitor moiety is present in aweight ratio of from about 1:10 to about 1:60 with respect to the weightof the polymeric moiety, preferably from about 1:20 to about 1:40, andmore preferably from about 1:25 to 1:35. In one aspect, such lipaseinhibitors comprise at least one lipase inhibitor moiety (or moieties)linked directly or indirectly to such polymeric moiety.

In another aspect the present invention relates to novel salts ofnon-absorbable lipase inhibitors and a non-absorbable biocompatible,pharmaceutically acceptable oil absorbing polymer. The invention alsoincludes pharmaceutical compositions comprising an effective amount ofsuch lipase inhibitors in combination with a pharmaceutically acceptablecarrier or diluent, which compositions may further comprise an effectiveamount of a lipophilic, non-absorbable biocompatible, pharmaceuticallyacceptable oil absorbing polymer.

In a preferred aspect the present invention relates to novel essentiallynon-absorbable derivatives of a 1,3 oxetanone lipase inhibitor, whichinclude at least one 1,3 oxetanone lipase inhibiting moiety that iscovalently or non-covalently linked to a non-absorbable biocompatible,pharmaceutically acceptable polymer moiety to provide a novel lipaseinhibitor compound. Preferred compounds have the dual function ofinhibiting lipases and absorbing fat, in that the non-absorbablebiocompatible, pharmaceutically acceptable polymer moiety of the novellipase inhibitor will bind to fat, carry the bound fat with it throughportions of the digestive system and cause the non-absorbed fat to beeliminated removed from the digestive system as undigested fat. Furtherpreferred are such compounds wherein the compound is capable ofassociating with both oil and water to form an essentially homogeneousgel. The 1,3 oxetanone moiety that is derivatized directly or indirectlywith the polymer moiety according to the invention may be initially anabsorbable or non-absorbable moiety and is derivatized by directly orindirectly linking it to the polymer moiety to form a novelnon-absorbable lipase inhibitor, preferably at the 5 hydroxyl positionof a 1,3 oxetanone moiety.

In a preferred aspect the invention provides compounds having eithernon-covalent linkages of such two moieties or covalent linkages that arehydrolyzed or digested in the digestive system, providing that thelipase inhibiting 1,3 oxetanone derivative moiety that is released inthe digestive system is substantially non-absorbable.

In one aspect of the invention, lipases such as esterastin moiety,tetrahydroestrastin, or a similar moiety, is coupled directly orindirectly to a non-absorbable biocompatible, pharmaceuticallyacceptable polymer moiety, such as a polysaccharide, to render thelipase essentially non-absorbable by the digestive system of an animalsuch as a dog, cat, non-human primate or humans. Preferred absorbablelipase inhibitor moieties that are rendered non-absorbable by suchcoupling include at least one lipase inhibitor which is a memberselected from the group consisting of esterastin, tetrahydro-esterastin(3,5-hydroxy-2-hexadeca-7,10-dienoic 1,3-lactone),3,5-dihydroxy-2-hexylhexadeca-7,10-dienoic 1,3-lactone,3,5-di-hydroxy-2-hexylhexadecanoic 1,3-lactone, and the like.Preferably, such lipase inhibitor is coupled to a non-absorbablebiocompatible, pharmaceutically acceptable polymer moiety, such as apolysaccharide, to render the lipase non-absorbable by the digestivesystem of an animal such as a dog, cat, non-human primate or humans.Particularly preferred polysaccharides have at least one member selectedfrom the group consisting of dextrans, molecular microcrystallinecellulose, wheat bran, oat bran, defatted rice germ, alginic acid,pectin, amylopectin, chitin, crude cellulose, argar, chitosan, achitosan methylbenzoic acid ester ether derivative, and the like.Particularly preferred bound lipase inhibitors are lipase inhibitorsbound via a derivatized group on the lipase such as a derivatizednitrogen, acid or alcohol group to a group on the polymer moiety such asa derivatized alcohol, acid or amino group. Preferably, amino groups,alcohol groups or both amino and alcohol groups on the polysaccharidehas been derivitized with a sufficient number of organic acyl groups torender the polysaccharide capable of associating with both oil and waterand thereby form an essentially homogeneous gel. Preferably, a terminalether/terminal acyl ester bridge or a terminal amino/terminal acyl esterbridge is formed between the lipase inhibitor and the moiety, whereinthe bridge is derived from an alcohol group on the lipase and an alcoholor amino group on the polysaccharide moiety, each reacting thepolysaccharide with an etherizing or amino forming bridging group topresent an acyl group, which may be a free acyl group or ester group.Also preferred are compounds wherein the oxetanone moiety of lipaseinhibitor is derivatized to provide an amino group which is furtherderivatized to form a carboxamide group, followed by linking thecarboxamide group to an acid, amino or alcohol group on the polymermoiety via a bridging group, which polymer moiety may have beenderivativized in order to provide such an acid, alcohol or amino groupfor attachment. Examples of such attachments are illustrated below bypreferred embodiments of the invention.

An ether terminal/ester terminal or amino terminal/ester terminal,between the lipase inhibitor moiety and the polymer moiety which isderived from an alcohol group on the lipase inhibitor moiety and analcohol or amino group on the polysaccharidemoiety, respectivelyreacting with a bridging group is a preferred coupling of the lipaseinhibitor to the moiety.

Another preferred bridge between the lipase inhibitor moiety and thepolymer moiety includes at least one ether bridge or amino bridge formedfrom an alcohol group or amino group, respectively, on the polymermoiety and at least one carboxamide bond. Further preferred are compoundwherein at least one amino acid derivative is located in the bridge, andis bound directly or indirectly to the 5 hydroxyl position on the 1,3oxetanone lipase inhibitor moiety via an ester linkage.

The preferred compounds also include their pharmaceutically acceptableisomers, hydrates, solvates, salts and prodrug derivatives.

A preferred aspect of the present invention relates to novel oxetanonederivatives of the formula I, as follows:

wherein:

t is an integer from 0 to 1

X-L-Q is an ether or amino linkage wherein:

X of the ether or amino linkage is a bridging group,

L is —O— or —NH—, and

Q of the ether or amino linkage is a polysaccharide of a sufficientmolecular weight or property that such polysaccharide is not absorbed bythe digestive system of a mammal such as a dog, cat, non-human primateor a human primate, particularly preferred is wherein the hydroxylgroups, amino groups or hydroxyl and amino groups of Q are modified bythe attachment of a sufficient number of organic acyl groups to cause Qto absorb or associate with both lipids and water and to form asubstantially homogeneous gel with lipids and water;

R is a member selected from the group consisting of:

a straight or branched chained C₁₋₁₇-alkyl group which is saturated oroptionally interrupted by up to eight double or triple bonds;

a straight or branched chained C₁₋₁₇-alkyl group which is saturated oroptionally interrupted by one or more members selected from the groupconsisting of an oxygen atom, a sulfur atom, a sulfonyl group or asulfinyl group;

a straight or branched chained C₁₋₁₇-alkyl group which is saturated oroptionally interrupted by up to eight double or triple bonds and isinterrupted in a position other than alpha to an unsaturated carbon atomby one or more members selected from the group consisting of an oxygenatom, a sulfur atom, a sulfonyl group or a sulfinyl group atoms;

phenyl substituted by 0-4 members selected from the group consisting of—C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl, —C₁₋₆-alkyl-OHand —C₁₋₆-alkyl-SH;

benzyl substituted by 0-4 members selected from the group consisting of—C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl, —C₁₋₆-alkyl-OHand —C₁₋₆-alkyl-SH;

biphenylene substituted by 0-6 members selected from the groupconsisting of —C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl,—C₁₋₆-alkyl-OH and —C₁₋₆-alkyl-SH;

phenoxyphenylene substituted by 0-6 members selected from the groupconsisting of —C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl,—C₁₋₆-alkyl-OH and —C₁₋₆-alkyl-SH;

phenylthiophenylene substituted by 0-6 members selected from the groupconsisting of —C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl,—C₁₋₆-alkyl-OH and —C₁₋₆-alkyl-SH; and

phenyl-C₁₋₆-alkyl-phenyl wherein 0-6 hydrogen atoms on one or more ofthe phenyl ring and —C₁₋₆-alkyl- group is/are replaced independently bya member selected from the group consisting of—C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl, —C₁₋₆-alkyl-OHand —C₁₋₆-alkyl-SH;

R¹ is a member selected from the group consisting of:

Hydrogen,

Ar,

Ar— C₁₋₅-alkyl and

C₁₋₁₀-alkyl interrupted by 0-3 members independently selected from thegroup consisting of an oxygen atom, a sulfur atom, a sulfinyl group, asulfonyl group, a-N(—R⁴)— group, a —C(═O)—N(—R⁴)— group, and a—N(—R⁴)—C(═O)— group, wherein 0-3 carbon atoms of the C₁₋₁₀-alkyl groupcan be substituted independently by a member selected from the groupconsisting of a hydroxy group, thiol group, C₁₋₁₀-alkoxy group, aC₁₋₁₀-alkylthio group, a —N(—R⁵,—R⁶) group, a —C(═O)—N(—R⁷, —R⁸) group,and a —N(—R⁹)—C(═O)—R¹⁰ group;

R² is a member selected from the group consisting of:

hydrogen and C₁₋₆-alkyl, or R² taken with R¹ forms a 4-6 memberedsaturated ring containing 0-4 nitrogen atoms wherein the ring may besubstituted by 0-4 R¹¹ groups;

R³ is a member selected from the group consisting of:

a straight or branched chained C₁₋₁₇-alkyl group which is saturated oroptionally interrupted by up to eight double or triple bonds;

a straight or branched chained C₁₋₁₇-alkyl group which is saturated oroptionally interrupted by one or more members selected from the groupconsisting of an oxygen atom, a sulfur atom, a sulfonyl group or asulfinyl group;

a straight or branched chained C₁₋₁₇-alkyl group which is saturated oroptionally interrupted by up to eight double or triple bonds and isinterrupted in a position other than alpha to an unsaturated carbon atomby one or more members selected from the group consisting of an oxygenatom, a sulfur atom, a sulfonyl group or a sulfinyl group atoms;

phenyl substituted by 0-4 members selected from the group consisting of—C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl, —C₁₋₆-alkyl-OHand —C₁₋₆-alkyl-SH;

benzyl substituted by 0-4 members selected from the group consisting of—C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl, —C₁₋₆-alkyl-OHand —C₁₋₆-alkyl-SH;

biphenylene substituted by 0-6 members selected from the groupconsisting of —C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl,—C₁₋₆-alkyl-OH and —C₁₋₆-alkyl-SH;

phenoxyphenylene substituted by 0-6 members selected from the groupconsisting of —C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl,—C₁₋₆-alkyl-OH and —C₁₋₆-alkyl-SH;

phenylthiophenylene substituted by 0-6 members selected from the groupconsisting of —C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl,—C₁₋₆-alkyl-OH and —C₁₋₆-alkyl-SH; and

phenyl-C₁₋₆-alkyl-phenyl wherein 0-6 hydrogen atoms on one or more ofthe phenyl ring and —C₁₋₆-alkyl- group is/are replaced independently bya member selected from the group consisting of—C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl, —C₁₋₆-alkyl-OHand —C₁₋₆-alkyl-SH;

R⁴-R¹⁰ are each independently a member selected from the groupconsisting of:

hydrogen and C₁₋₆-alkyl;

n is an integer of 0-3;

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

Another preferred aspect of the present invention relates to noveloxetanone derivatives of the formula Ia, as follows:

wherein:

t is an integer from 0 to 1

X—N(—H)-Q is an amino linkage of X to Q wherein:

X of the amino linkage is a bridging group, and

Q of the amino linkage is a polysaccharide of a sufficient molecularweight or property that such polysaccharide is not absorbed by thedigestive system of a mammal such as a dog, cat, non-human primate or ahuman primate, particularly preferred is wherein the hydroxyl groups,amino groups or hydroxyl and amino groups of Q are modified by theattachment of a sufficient number of organic acyl groups to cause Q toabsorb or associate with both lipids and water and to form asubstantially homogeneous gel with lipids and water;

R is a member selected from the group consisting of:

a straight or branched chained C₁₋₁₇-alkyl group which is saturated oroptionally interrupted by up to eight double or triple bonds;

a straight or branched chained C₁₋₁₇-alkyl group which is saturated oroptionally interrupted by one or more members selected from the groupconsisting of an oxygen atom, a sulfur atom, a sulfonyl group or asulfinyl group;

a straight or branched chained C₁₋₁₇-alkyl group which is saturated oroptionally interrupted by up to eight double or triple bonds and isinterrupted in a position other than alpha to an unsaturated carbon atomby one or more members selected from the group consisting of an oxygenatom, a sulfur atom, a sulfonyl group or a sulfinyl group atoms;

phenyl substituted by 0-4 members selected from the group consisting of—C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl, —C₁₋₆-alkyl-OHand —C₁₋₆-alkyl-SH;

benzyl substituted by 0-4 members selected from the group consisting of—C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl, —C₁₋₆-alkyl-OHand —C₁₋₆-alkyl-SH;

biphenylene substituted by 0-6 members selected from the groupconsisting of —C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl,—C₁₋₆-alkyl-OH and —C₁₋₆-alkyl-SH;

phenoxyphenylene substituted by 0-6 members selected from the groupconsisting of —C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl,—C₁₋₆-alkyl-OH and —C₁₋₆-alkyl-SH;

phenyithiophenylene substituted by 0-6 members selected from the groupconsisting of —C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl,—C₁₋₆-alkyl-OH and —C₁₋₆-alkyl-SH; and

phenyl-C₁₋₆-alkyl-phenyl wherein 0-6 hydrogen atoms on one or more ofthe phenyl ring and —C₁₋₆-alkyl- group is/are replaced independently bya member selected from the group consisting of—C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl, —C₁₋₆-alkyl-OHand —C₁₋₆-alkyl-SH;

R¹ is a member selected from the group consisting of:

Hydrogen,

Ar,

Ar— C₁₋₅-alkyl and

C₁₋₁₀-alkyl interrupted by 0-3 members independently selected from thegroup consisting of an oxygen atom, a sulfur atom, a sulfinyl group, asulfonyl group, a-N(—R⁴)— group, a —C(═O)—N(—R⁴)— group, and a—N(—R⁴)—C(═O)— group, wherein 0-3 carbon atoms of the C₁₋₁₀-alkyl groupcan be substituted independently by a member selected from the groupconsisting of a hydroxy group, thiol group, C₁₋₁₀-alkoxy group, aC₁₋₁₀-alkylthio group, a —N(—R⁵,—R⁶) group, a —C(═O)—N(—R⁷, —R⁸) group,and a —N(—R⁹)—C(═O)—R¹⁰ group;

R² is a member selected from the group consisting of:

hydrogen and C₁₋₆-alkyl, or R² taken with R¹ forms a 4-6 memberedsaturated ring containing 0-4 nitrogen atoms wherein the ring may besubstituted by 0-4 R¹¹ groups;

R³ is a member selected from the group consisting of:

a straight or branched chained C₁₋₁₇-alkyl group which is saturated oroptionally interrupted by up to eight double or triple bonds;

a straight or branched chained C₁₋₁₇-alkyl group which is saturated oroptionally interrupted by one or more members selected from the groupconsisting of an oxygen atom, a sulfur atom, a sulfonyl group or asulfinyl group;

a straight or branched chained C₁₋₁₇-alkyl group which is saturated oroptionally interrupted by up to eight double or triple bonds and isinterrupted in a position other than alpha to an unsaturated carbon atomby one or more members selected from the group consisting of an oxygenatom, a sulfur atom, a sulfonyl group or a sulfinyl group atoms;

phenyl substituted by 0-4 members selected from the group consisting of—C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl, —C₁₋₆-alkyl-OHand —C₁₋₆-alkyl-SH;

benzyl substituted by 0-4 members selected from the group consisting of—C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl, —C₁₋₆-alkyl-OHand —C₁₋₆-alkyl-SH;

biphenylene substituted by 0-6 members selected from the groupconsisting of —C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl,—C₁₋₆-alkyl-OH and —C₁₋₆-alkyl-SH;

phenoxyphenylene substituted by 0-6 members selected from the groupconsisting of —C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl,—C₁₋₆-alkyl-OH and —C₁₋₆-alkyl-SH;

phenylthiophenylene substituted by 0-6 members selected from the groupconsisting of —C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl,—C₁₋₆-alkyl-OH and —C₁₋₆-alkyl-SH; and

phenyl-C₁₋₆-alkyl-phenyl wherein 0-6 hydrogen atoms on one or more ofthe phenyl ring and —C₁₋₆-alkyl- group is/are replaced independently bya member selected from the group consisting of—C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl, —C₁₋₆-alkyl-OHand -C₁₋₆-alkyl-SH;

R⁴-R¹⁰ are each independently a member selected from the groupconsisting of:

hydrogen and C₁₋₆-alkyl;

n is an integer of 0-3;

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

A preferred compound according to formula I, or formula Ia, is acompound wherein X is a member selected from the group consisting of:

—(C(═O))₀₋₁—X_(a)—,

wherein X_(a) is a member selected from the group consisting of:

a straight or branched chained divalent C₁₋₁₇-alkylene group which issaturated or optionally interrupted by up to eight double or triplebonds;

a straight or branched chained divalent C₁₋₁₇-alkylene group which issaturated or optionally interrupted by one or more members selected fromthe group consisting of:

an oxygen atom,

a sulfur atom,

a sulfonyl group,

a sulfinyl group,

a substituted or unsubstituted 6-10 member monocyclic or bicyclic arylor heteroaryl group having from 1-4 ring hetero atoms selected from thegroup consisting of O, N, S,

a —NH— group, wherein the hydrogen atom may be replaced with a C₁₋₁₀alkyl group

a —C(═O)— group,

a —NH—C(═O)— group, wherein the hydrogen atom may be replaced with aC₁₋₁₀ alkyl group and

a —C(═O)—NH— group, wherein the hydrogen atom may be replaced with aC₁₋₁₀ alkyl group

a straight or branched chained divalent C₁₋₁₇-alkylene group which issaturated or optionally interrupted by up to eight double or triplebonds and is interrupted in a position other than alpha to anunsaturated carbon atom by one or more members selected from the groupconsisting optionally interrupted by one or more members selected fromthe group consisting of:

an oxygen atom,

a sulfur atom,

a sulfonyl group,

a sulfinyl group,

a substituted or unsubstituted 6-10 member monocyclic or bicyclic arylor heteroaryl group having from 1-4 ring hetero atoms selected from thegroup consisting of O, N, S,

a —NH— group, wherein the hydrogen atom may be replaced with a C₁₋₁₀alkyl group

a —C(═O)— group,

a —NH—C(═O)— group, wherein the hydrogen atom may be replaced with aC₁₋₁₀ alkyl group and

a —C(═O)—NH— group, wherein the hydrogen atom may be replaced with aC₁₋₁₀ alkyl group

divalent phenylene or divalent naphthylene substituted on the ringstructure by 0-4 members selected from the group consisting of—C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl, —C₁₋₆-alkyl-OHand —C₁₋₆-alkyl-SH;

divalent biphenylene substituted by 0-6 members selected from the groupconsisting of —C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl,—C₁₋₆-alkyl-OH and —C₁₋₆-alkyl-SH;

phenoxyphenylene substituted by 0-6 members selected from the groupconsisting of —C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl,—C₁₋₆-alkyl-OH and —C₁₋₆-alkyl-SH;

divalent phenylthiophenylene substituted by 0-6 members selected fromthe group consisting of —C₁₋₆-alkyloxy-C₁₋₆-alkyl,—C₁₋₆-alkylthio-C₁₋₆-alkyl, —C₁₋₆-alkyl-OH and —C₁₋₆-alkyl-SH; and

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

Preferred sub-groups of such compounds are compounds wherein R is—(CH₂)₃₋₆—CH₃ and R³ is a member selected from the group consisting of—(CH₂)₈₋₁₄—CH₃ and —CH₂—CH═CH—CH₂—CH═CH—(CH₂)₂₋₈—CH₃. Even morepreferred are such compounds wherein R is —(CH₂)₅—CH₃ and R³ is a memberselected from the group consisting of —(CH₂)₁₀—CH₃ and—CH₂—CH═CH—CH₂—CH═CH—(CH₂)₄—CH₃.

In a preferred embodiment, the present invention relates to noveloxetanone derivatives wherein n of the above formula is zero to providecompounds of the formula:

wherein:

X, L, t, Q, R, R¹, R² and R³ are defined as above, and isomers, salts,hydrates, solvates and prodrug derivatives thereof. Preferred sub-groupsof such compounds are compounds wherein R is —(CH₂)₃₋₆—CH₃ and R³ is amember selected from the group consisting of —(CH₂)₈₋₁₄—CH₃ and—CH₂—CH═CH—CH₂—CH═CH—(CH₂)₂₋₈—CH₃. More preferred are such compoundswherein R is —(CH₂)₅—CH₃ and R³ is a member selected from the groupconsisting of —(CH₂)₁₀—CH₃ and —CH₂—CH═CH—CH₂—CH═CH—(CH₂)₄—CH₃. Furtherpreferred are compounds wherein t is 0 and X is —C(═O)—X_(a)— as setforth above.

Even further preferred are such compounds wherein t is 1 and X is amember selected from the group consisting of:

wherein R^(1a) is independently defined the same as defined for R¹,R^(2a) is independently defined the same as for R², m is a integer from0 to 10, preferably from 0-5, and more preferred from 0-2, and wherein zis an integer from 1 to 20, preferably 2 to 10, and more preferably,2-4, and all pharmaceutically acceptable isomers, salts, hydrates,solvates and prodrug derivatives thereof.

In another preferred embodiment, the present invention relates to suchnovel oxetanone derivatives of formula 1 having the following formula:

wherein:

X, L, Q, R, and R³ are defined as above, and isomers, salts, hydrates,solvates and prodrug derivatives thereof. Preferred sub-groups of suchcompounds are compounds wherein R is —(CH₂)₃₋₆—CH₃ and R³ is a memberselected from the group consisting of —(CH₂)₈₋₁₄—CH₃ and—CH₂—CH═CH—CH₂—CH═CH—(CH₂)₂₋₈—CH₃. More preferred are such compoundswherein R is —(CH₂)₅—CH₃ and R³ is a member selected from the groupconsisting of —(CH₂)₁₀—CH₃ and —CH₂—CH═CH—CH₂—CH═CH—(CH₂)₄—CH₃.

Even further preferred are such compounds wherein X is a member selectedfrom the group consisting of:

wherein z is a integer from 0 to 10, preferably from 0-5, and morepreferred from 0-2.

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

Other preferred compounds are compounds, wherein t is 0 or 1 and X is amember selected from the group consisting of:

wherein R^(1a) is independently defined the same as defined for R¹,R^(2a) is independently defined the same as for R², m is a integer from0 to 10, preferably from 0-5, and more preferred from 0-2, and wherein zis an integer from 1 to 20, preferably 2 to 10, and more preferably,2-4, and all pharmaceutically acceptable isomers, salts, hydrates,solvates and prodrug derivatives thereof. One preferred group ofcompounds are such compounds wherein L is —NH— and another preferredgroup of compounds are such compounds wherein L is —O—.

The above compound, wherein X is a member selected from the groupconsisting of:

and wherein z is a integer from 0 to 10, preferably from 0-5, and morepreferred from 0-2,

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof.

Further preferred are such compounds, wherein X is a member selectedfrom the group consisting of:

and wherein z is a integer from 0 to 18,

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof. One preferred group of such compoundsis wherein L is —NH— and another preferred group of such compound iswherein L is —O—.

Additionally preferred are such compounds wherein X is a member selectedfrom the group consisting of:

and wherein z is a integer 6-12,

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof. One preferred group of such compoundsis wherein L is —NH— and another preferred group of such compound iswherein L is —O—.

More preferred are such compounds wherein X is a member selected fromthe group consisting of:

and wherein z is a integer 6-12,

and all pharmaceutically acceptable isomers, salts, hydrates, solvatesand prodrug derivatives thereof. One preferred group of such compoundsis wherein L is —NH— and another preferred group of such compound iswherein L is —O—.

Particularly preferred Q groups for the above compounds arenon-absorbable biocompatable, pharmaceutically acceptable polymers, suchas a polysaccharide, which are preferably lipophilic and bind to fat andare non-absorbable by the digestive system of an animal such as a dog,cat, non-human primate or humans. Particularly preferred polysaccharideshave at least one member selected from the group consisting of dextrans,molecular microcrystalline cellulose, wheat bran, oat bran, defattedrice germ, alginic acid, pectin, amylopectin, chitin, crude cellulose,argar, chitosan and the like. Particularly preferred Q groups have analcohol, acyl group or amino group, or can be derivitized to presentsuch an alcohol, acyl or amino group, which can be bound to the R moietyor the X—R—X group Preferably, at least one and or two ether bridges canbe formed between a lipase inhibitor moiety and the polymer moiety viaan X—R—X bridge, wherein the bridge is derived from an alcohol group oramine group on the lipase and an alcohol group, acyl group or aminogroup on the Q group. Even more preferred are Q groups which arechitosan derivatives that have been modified by an ether group or aminogroup which is terminated by an organic acid group. Further preferredare such modified chitosan Q groups wherein the organic acyl groupsappended from the modified alcohol or amino group of the polysaccharideare independently a straight or branched chained alkanoyl group. Mostpreferred are such modified chitosan Q groups wherein the polarityresulting from the modification of chitosan alcohol or amino groups withorganic acyl groups allows the modified chitosan to absorb both lipidsand water and to form a substantially homogenous gel with lipids andwater.

Most preferred are the compounds as set forth above, wherein the Q groupis a chitosan compound modified with a sufficient number of organic acylgroups to cause the modified chitosan to absorb or associate both lipidsand water and to form a substantially homogenous gel with oil and water.The number of organic acyl groups present on the modified chitosanchains are present in a molar ratio from 1 to 8 times the number of themolar ratio of esterified lipase inhibitor alcohol groups, and morepreferably a ratio from 2 to 5 times, and most preferably a ratio offrom 3 to 4 times the number of esterified lipase inhibitor alcoholgroups.

Preparation of Compounds

The lipase inhibitor compounds, polymer moieties and bridging groups ofthe present invention may be synthesized or readily obtained fromcommercially available sources. Polymer bridging groups, bridge couplingprocesses and compound purification methods are described and referencedin standard textbooks, particularly the coupling of alcohol groups viadiether bridges, ether/ester bridges, ether/ketone bridges and the like.Standard polymer textbooks reference typical bifunctional bridginggroups and coupling procedures.

Starting materials used in any of these methods are commerciallyavailable from chemical vendors such as Aldrich, Sigma, NovaBiochemicals, Bachem Biosciences, and the like, or may be readilysynthesized by known procedures.

Reactions are carried out in standard laboratory glassware and reactionvessels under reaction conditions of standard temperature and pressure,except where otherwise indicated.

During the synthesis of these compounds, the functional groups may beprotected by blocking groups to prevent cross reaction during thecoupling procedure. Examples of suitable blocking groups and their useare described in “The Peptides: Analysis, Synthesis, Biology”, AcademicPress, Vol. 3 (Gross, et al., Eds., 1981) and Vol. 9 (1987), thedisclosures of which are incorporated herein by reference.

Lipase inhibitor moieties having a free hydroxy group such astetrahydro-esterastin (3,5-hydroxy-2-hexadeca-7,10-dienoic 1,3-lactone),3,5-dihydroxy-2-hexylhexadeca-7,10-dienoic 1,3-lactone,3,5-di-hydroxy-2-hexylhexadecanoic 1,3-lactone, and the like, are easilycoupled to a polymer moiety having free hydroxy groups such ascellulose, chitosan and other polysaccharides having free hydroxylgroups. One or both of the lipase inhibitor moiety and the polymermoiety may be derivitized to form part of the linking bridge prior toreacting with the other moiety. For example, the lipase inhibitormolecule may be condensed with a dihalide group or a terminal halideterminal acyl (acyl group may be protected with an acid group) to forman ether or ester linkage and then condensed with a polymer moietyhaving a free hydroxyl group or free amino group by methods shown inpolymer chemistry. In one procedure a polymer moiety such as chitosancan be reacted with a compound such as a halomethylbenzoic acid ester,C₂ to C₂₀ n-haloalkanoic acid, C₂ to C₂₀ n-alkanoic acid ester or thelike, and optionally de-esterified to present a free acid group whichmay be reacted to form an ester, ketone, carboxamide or the like withthe derivitized or underivatized lipase inhibitor moiety. In onepreferred aspect of the invention, the amino or alcohol groups of thepolysaccharide moiety, such as chitosan, is reacted with one or moretypes of n-haloalkanoic acid (or an acyl ester derivative) such asn-bromohexanoic acid, n-chlorolauric acid in a molar ratio 1:1 to 1:10,or the like, sufficient to attach an organic acyl side chain to 1 to10%, preferably from 1 to 5% and more preferably from 2 to 4%, of thefree alcohol groups, amino groups or alcohol and amino groups on thepolysaccharide chain to provide an organic acyl group modifiedpolysaccharide, such as an organic acyl group modified chitosanderivative. In such case, the n-haloalkanoic acid, or other haloderivative organic acyl group, etherizes free hydroxyl groups, replacesa hydrogen atom on an amino group, or forms a ketone with an acid groupor a previously modified polysaccharide compound, and the resultingintermediate can then be reacted with the lipase inhibitor to form anester group with a free alcohol group, replace a hydrogen atom on aamino group to form a carboxamide, and the like. Particularly preferredpolymer moieties to be modified are polysaccharides having multiple freehydroxyl groups or amino groups for coupling, such as chitosan or achitosan that has optionally been sulfonated to render the lipase moietyitself a lipase inhibitor compound. Etherification, amination and ketoneformation procedures are well-known in the art and well within theroutine skill of the ordinary practitioner. Further, other bridginggroups and the techniques for binding a compound having a reactivefunctional group to a polymer moiety are well-known in the art. Thepreferred compounds also include their pharmaceutically acceptableisomers, hydrates, solvates, salts and prodrug derivatives.

The bridging group refers to a bifunctional chain or spacer groupcapable of reacting with one or more functional groups on a lipaseinhibitor compound and then react with a second same or differentfunctional group on a polymer compound in order to form a linkedstructure or conjugate between the two compounds. The bond formedbetween the bridging group and each of the two compounds is preferablyof a type that is resistant to cleavage by the digestive environment,except that the lipase inhibitor may optionably be cleavable by adigestive lipase. In one aspect, the bridging group is of the formulaX—R—X, wherein R is a member selected from a straight-chained orbranched alkyl group, a straight-chained or branched alkenyl group, astraight-chained or branched alkynyl group, a mono acyl group, a diacylgroup and the like, and X is a functionally reactive group such as ahalogen or an acid group, preferably on X is bromo and the other is anacyl or acyl ester group, which react under the special reactionconditions as described hereinafter. Particularly preferred bridginggroups form a terminal ether or a terminal amino alkyl bond with thepolysaccharide and an acyl ester or carboxamide bond with the lipaseinhibitor.

Examples of alkylene dichloride bridging group forming compounds aredichloromethane, 1,2-dichloroethane, 1,2- and 1,3-dichloropropane, 1,2-,1,3- and 1,4-dichlorobutane, 1,2-bromochloroethane, 1,2-and1,3-bromochloropropane, and the like.

Examples of acyldichloride bridging group forming compounds are oxalicacid dichloride, malonic acid dichloride, succinic acid dichloride,glutaric acid dichloride, adipic acid dichloride, pimelic aciddichloride, suberic acid dichloride, fumaric acid dichloride, malic aciddichloride, glutamic acid dichloride, terephthalic acid dichloride,isophthalic acid dichloride, and the like.

Examples of haloacyl bridging groups include chloromethylbenzoic acid oran ester thereof, 3-bromopropanoic acid, 2-chloroacetic acid,6-bromohexanoic acid or an ester thereof, 12-bromododecanoic acid or anester thereof, other n-haloalkanoic acids or esters thereof, and thelike.

Other such bridging group reagents are compounds such as epichlorhydrin,phosphorus oxychloride, and diphosphoryl tetrachloride, and the like.

Preferred bridging groups terminated with at least one bromo or chlorinegroup and the other terminus is an acyl group or an acyl derivative.Even more preferred bridging groups are n-halo(preferablyn-bromo)-C₄-C₂₀ (preferably C₆-C₁₄) alkanoic acids or esters thereof.The reaction is reacting the bridging group with the polysaccharideunder either etherification or amino alkylation conditions in asubstantially water immiscible organic solvent, such as THFsubstantially 1:1 to 1:10 molecular ratio of polysaccharide chain tobridging group reactant. The reaction may proceed at the interfacebetween the two immiscible solutions, or in solution, to provide acondensation and produce the polysaccharide derivative or analogue. Ithas been discovered that this reaction at the interface of the organicsolution and the aqueous solution imparts a specificity to the reactionfor primary alcohol groups of the polysaccharide. A miscible solventsuch as THF, an ether or the like, favors alkylation of the aminogroups. It should be understood that equivalent reactants such asdiepoxides and balohydrocarbyloxiranes such as epichlorohydrin alsoreact in the process to provide new and useful ether bridges.

By appropriate selection of the type of bridging group reactant andreaction conditions, different structural groups with various chemicalproperties can be incorporated into the resulting bridge and varioustypes of lipase inhibitors can be connected to a nonabsorbable polymermoiety, such as a polysaccharide, and preferably to chitosan or modifiedchitosan. Reaction temperatures and other reactions conditions, as wellare reactant proportions are well within the skill of the ordinarypolymer chemist practitioner in view of the present description of theinvention. Other groups and modifications will be apparent to one ofordinary skill in the art from the above discussion.

The lipase inhibitor functionality of the coupled lipase inhibitors maybe determined by well-known lipase inhibitor assays. A therapeuticallyeffective amount of the bound lipase inhibitor may be administered to apatient. Additional fat binding polymers may optionally be added to thecomposition.

The following non-limiting reaction Schemes I, II, III and IV illustratepreferred embodiments of the invention with respect to making compoundsaccording to the invention.

Therefore, in a preferred aspect the invention provides a method forproducing a compound of claim 1, comprising reacting a compound of theformula:

with a compound of the formula

wherein L is —O— or —NH—, t is 0 or 1 and Y is a leaving group for anetherification or esterification reaction with the hydroxy group toproduce a compound of the formula:

or a salt thereof.

Pharmaceutical Compositions and Edible Compositions

In one aspect, the present invention provides a sports drink, snack,nutrient supplement, food or power which may be formulated to contain alipase inhibiting therapeutically effective amount of the lipaseinhibitor composition according to the invention.

In another aspect the present invention relates to pharmaceuticalcompositions comprising a lipase inhibiting effective amount of at leastone lipase inhibitor which is coupled to a digestively non-absorbablemoiety. Preferred are such pharmaceutical compositions comprising aneffective amount of a lipases coupled to a non-absorbable biocompatable,pharmaceutically acceptable polymer moiety, such as a polysaccharide,wherein the lipase is essentially non-absorbable by the digestive systemof an animal such as a dog, cat, non-human primate or humans. Thepharmaceutical composition can be administrated to a patent prior to orwithin one hour of consuming a fat-containing meal to prevent absorptionof up to one-third of the dietary fat consumed at the meal.

In still another aspect, the present invention relates to a method fortreating adiposity or obesity by administering to a patient before afat-contain meal, or up to one hour after such a meal is consumed, anamount of at least one lipase inhibitor which is bound to anon-absorbable polymer moiety in an amount effective to inhibit theabsorption of up to one-third of the dietary fat in such a meal. Inparticular, a preferred method comprises administering at one lipaseinhibitor which is a member selected from the group consisting ofesterastin, tetrahydro-esterastin (3,5-hydroxy-2hexadeca-7,10-dienoic1,3-lactone), 3,5-dihydroxy-2-hexylhexadeca-7, 10-dienoic 1,3-lactone,3,5-di-hydroxy-2-hexylhexadecanoic 1,3-lactone, and the like, whereinsuch lipase inhibitor is coupled to a non-absorbable biocompatable,pharmaceutically acceptable polymer moiety, such as a polysaccharide, torender the lipase non-absorbable by the digestive system of an animalsuch as a dog, cat, non-human primate or humans. Particularly preferredpolysaccharides are at least one member selected from the groupconsisting of dextrans, molecular microcrystalline cellulose, wheatbran, oat bran, defatted rice germ, alginic acid, pectin, amylopectin,chitin, crude cellulose, argar, chitosan and the like. Particularlypreferred bound lipase inhibitors are lipase inhibitors bound via aderivatized nitrogen, acid or alcohol group to a derivatized alcohol,acid or amino group on the polymer moiety. Preferred bound polymermoities are derivatized to have an excess of acyl organic acid sidechains which are adequate to cause the compound to absorb both oil andwater or associate with both oil and water to provide a substantiallyhomogeneous gel. A ether bond or alkylamino bond at one bridge terminusand an acyl ester or carboxamide bridge terminus connecting the lipaseinhibitor and the polysaccharide moiety is preferred which is derivedfrom an alcohol group on the lipase and an alcohol or amino group on thepolysaccharide moiety, respectively reacting with a bridging group isthe preferred coupling of the lipase inhibitor to the moiety.

The compounds of this invention may be isolated as the free acid or baseor converted to salts of various inorganic and organic acids and bases.Such salts are within the scope of this invention. Non-toxic andphysiologically compatible salts are particularly useful although otherless desirable salts may have use in the processes of isolation andpurification.

Numerous methods are useful for the preparation of the salts describedabove and are known to those skilled in the art. For example, free acidor free base forms of a compound of one of the above compounds can bereacted with one or more molar equivalents of the desired acid or basein a solvent or solvent mixture in which the salt is insoluble, or in asolvent like water after which the solvent is removed by evaporation,distillation or freeze drying.

Alternatively, the free acid or base form of the product may be passedover an ion exchange resin to form the desired salt or one salt form ofthe product may be converted to another using the same general process.

Prodrug Derivatives of Compounds

This invention also encompasses prodrug derivatives of the compoundscontained herein. The term “prodrug” refers to a pharmacologicallyinactive derivative of a parent drug molecule that requiresbiotransformation, either spontaneous, acid/base reaction, or enzymatic,within the organism to release the active drug. Prodrugs are variationsor derivatives of the compounds of this invention which have groupscleavable under digestive system conditions. Prodrugs become thecompounds of the invention which are pharmaceutically active in vivo,when they undergo solvolysis under physiological conditions or undergoenzymatic degradation. Prodrug compounds of this invention may be calledsingle, double, triple etc., depending on the number ofbiotransformation steps required to release the active drug within theorganism, and indicating the number of functionalities present in aprecursor-type form. Prodrug forms often offer advantages of solubility,digestive compatibility, or delayed release in the mammalian organism(see, Bundgard, Design of Prodrugs, pp. 7-9, 21-24, Elsevier, Amsterdam1985 and Silverman, The Organic Chemistry of Drug Design and DrugAction, pp. 352-401, Academic Press, San Diego, Calif., 1992). Prodrugscommonly known in the art include acid derivatives well known topractitioners of the art, such as, for example, esters prepared byreaction of the parent acids with a suitable alcohol, or amides preparedby reaction of the parent acid compound with an amine, or basic groupsreacted to form an acylated base derivative. Moreover, the prodrugderivatives of this invention may be combined with other features hereintaught to enhance bioavailability.

Formulations of the compounds of this invention are prepared for storageor administration by mixing the compound having a desired degree ofpurity with physiologically acceptable carriers, excipients, stabilizersetc., and may be provided in sustained release or timed releaseformulations. Acceptable carriers or diluents for therapeutic use arewell known in the pharmaceutical field, and are described, for example,in Remington's Pharmaceutical Sciences, Mack Publishing Co., (A.R.Gennaro edit. 1985). Such materials are nontoxic to the recipients atthe dosages and concentrations employed, and include buffers such asphosphate, citrate, acetate and other organic acid salts, antioxidantssuch as ascorbic acid, low molecular weight (less than about tenresidues) peptides such as polyarginine, proteins, such as serumalbumin, gelatin, or immunoglobulins, hydrophilic polymers such aspolyvinylpyrrolidinone, amino acids such as glycine, glutamic acid,aspartic acid, or arginine, monosaccharides, disaccharides, and othercarbohydrates including cellulose or its derivatives, glucose, mannoseor dextrins, chelating agents such as EDTA, sugar alcohols such asmannitol or sorbitol, counterions such as sodium and/or nonionicsurfactants such as Tween, Pluronics or polyethyleneglycol.

Dosage formulations of the compounds of this invention to be used fortherapeutic administration must be sterile. Sterility is readilyaccomplished by filtration through sterile membranes such as 0.2 micronmembranes, or by other conventional methods. Formulations typically willbe stored in lyophilized form or as an aqueous solution. The pH of thepreparations of this invention typically will be 3-11, more preferably5-9 and most preferably 7-8. It will be understood that use of certainof the foregoing excipients, carriers, or stabilizers will result in theformation of cyclic polypeptide salts.

Therapeutically effective dosages may be determined bv either in vitroor in vivo methods. For each particular compound of the presentinvention, individual determinations may be made to determine theoptimal dosage required. The range of therapeutically effective dosageswill be influenced by the route of administration, the therapeuticobjectives and the condition of the patient. Accordingly, it may benecessary for the therapist to titer the dosage and modify the means ofadministration as required to obtain the optimal therapeutic effect. Thedetermination of effective dosage levels, that is, the dosage levelsnecessary to achieve the desired result, will be readily determined byone skilled in the art. Typically, applications of compound arecommenced at lower dosage levels, with dosage levels being increaseduntil the desired effect is achieved.

The compounds of the invention can be administered orally in aneffective amount within the dosage range of about 10 to 400 mg/kg,preferably about 20 to 200 mg/kg and more preferably about 20 to 50mg/kg per fat containing meal on a regimen in a single or 2 to 4 divideddaily doses. A preferred dosage is an amount (e.g. about 20 to 40 mg/kg)that has a similar lipase inhibiting effect to the lipase inhibition of120 mg (approximately 1-2 mg/kg dosage) of orally taken Orlistat. Thedetermination of such equivalent lipase inhibition can be determined viawell-known lipase inhibition assays, and may be either an in vivo assay,an in vitro assay, or both. The fat absorption properties of thelipophilic lipase inhibitor of the invention can be observed bycomparing the amount of anal oil discharged in a patient taking anlipase inhibitor equivalent amount of the lipase inhibitor according tothe invention as compared to a patient taking only Orlistat. Thegrooming of mice with anal oil is one comparison as compared to Orlistator the actual comparison of anal discharge in animals or patients alsowill show a reduction in the amount of oily anal discharge when alipophilic lipase inhibitor according to the invention is administered.

Typically, for a unit dose form, about 500 mg to 2 g of a compound ormixture of compounds of this invention, as the free acid or base form oras a pharmaceutically acceptable salt, is compounded with aphysiologically acceptable vehicle, carrier, excipient, binder,preservative, stabilizer, dye, flavor etc., as called for by acceptedpharmaceutical practice. The amount of active ingredient in thesecompositions is such that a suitable dosage in the range indicated isobtained.

Typical adjuvants which may be incorporated into tablets, capsules andthe like are binders such as acacia, corn starch or gelatin, andexcipients such as microcrystalline cellulose, disintegrating agentslike corn starch or alginic acid, lubricants such as magnesium stearate,sweetening agents such as sucrose or lactose, or flavoring agents. Whena dosage form is a capsule, in addition to the above materials it mayalso contain liquid carriers such as water, saline, or a fatty oil.Other materials of various types may be used as coatings or as modifiersof the physical form of the dosage unit. Sterile compositions forinjection can be formulated according to conventional pharmaceuticalpractice. For example, dissolution or suspension of the active compoundin a vehicle such as an oil or a synthetic fatty vehicle like ethyloleate, or into a liposome may be desired. Buffers, preservatives,antioxidants and the like can be incorporated according to acceptedpharmaceutical practice.

In certain aspects of this invention, compounds are provided which areuseful as diagnostic reagents to determine lipase activity. In anotheraspect, the present invention includes pharmaceutical compositionscomprising a pharmaceutically effective amount of the compounds of thisinvention and a pharmaceutically acceptable carrier. In yet anotheraspect, the present invention includes methods comprising using theabove compounds and pharmaceutical compositions for preventing ortreating disease states characterized by undesired lipid or fatabsorption such as obesity, hyperlipaemia, atherosclerosis andateioscherosis disorders of the blood coagulation process in mammals, orfor stabilizing fats by preventing lipase function in stored fatproducts and samples. Optionally, the methods of this invention compriseadministering the pharmaceutical composition in combination with anadditional therapeutic agent such as an anticholesterol agent, appetitesuppressant, metabolic stimulant and the like.

The preferred compounds also include their pharmaceutically acceptableisomers, hydrates, solvates, salts and prodrug derivatives.

In one embodiment the present invention provides a pharmaceuticalcomposition comprising at least one pharmaceutically acceptable carrierexcipient and an amount of at least one of the above described compoundsaccording to the invention in a therapeutically effective amount withrespect to limiting or preventing the absorption of some dietary fat. Ina preferred embodiment, the pharmaceutical composition comprises atherapeutically effective amount of slow-release lipoprotein lipase,preferably from a microbial or plant source, which selectivelyhydrolyzes terminal triglyceride groups in combination with an oilabsorbing effective amount of polysaccharide such as chitosan, whereinthe lipoprotein lipase is present in a ratio of less that 25% withrespect to the oil absorbing polysaccharide.

In another embodiment the present invention provides a pharmaceuticalcomposition comprising at least one pharmaceutically acceptable carrierexcipient, an amount of at least one of the above described compoundsaccording to the invention in a therapeutically effective amount withrespect to limiting or preventing the absorption of some dietary fat,and an oil absorbing effective amount of polysaccharide such aschitosan, wherein such lipase inhibitor is selectively effective toinhibit lipases other than lipases involved in the hydrolysis ofterminal triglyceride groups and such lipase inhibitor does notsubstantially inhibit the absorption of vitamins A, D and E.

In another embodiment the present invention provides a method of usingsuch compounds and pharmaceutical compositions as therapeutic agents fordisease states in a mammal having at least one disorder that is due toundesired absorption of dietary fat or for reducing the effectivecaloric intake of a mammal who consumes dietary fat, which method may beuseful in the treatment of undesired weight gain or obesity.

The compounds of this invention also find utility as intermediates forproducing therapeutic agents or as therapeutic agents for disease statesin mammals which have disorders that are due to undesired absorption ofdietary fat. Methods for making starting materials may be found in U.S.Pat. No. 4,931,463, which is incorporated fully herein. Preferredoxetanones of the invention are compounds wherein R is methyl, ethyl,propyl, hexyl, decyl, hexadecyl, allyl and benzyl, and most preferablyhexyl; R¹ is hydrogen, methyl, ethyl, propyl, 2-butyl, isobutyl, benzyland methylthio-ethyl, most preferably, hydrogen or isobutyl; R² ishydrogen, methyl or ethyl, most preferably hydrogen; n is 0 or 1, andwhen t is 1, then X is preferably attached to N via an amino acid, suchas valine, alanine and the like, preferably alanine; and R³ ispreferably a straight or branched chained C₁₋₁₇-alkyl group which issaturated or optionally interrupted by up to eight double or triplebonds, or R³ is a straight or branched chained C₁₋₁₇-alkyl group whichis saturated or optionally interrupted by one or more members selectedfrom the group consisting of an oxygen atom, a sulfur atom, a sulfonylgroup or a sulfinyl group or R³ is a straight or branched chainedC₁₋₁₇-alkyl group which is saturated or optionally interrupted by up toeight double or triple bonds and is interrupted in a position other thanalpha to an unsaturated carbon atom by one or more members selected fromthe group consisting of an oxygen atom, a sulfur atom, a sulfonyl groupor a sulfinyl group atoms.

The compounds produced according to the present invention, particularly,the modified polysaccharides, may also be used as intermediates in theformation of compounds that may be administered in combination or inconcert with other therapeutic or diagnostic agents, however, they maybe useful as oil absorbing polymers that are capable of dispersing inwater after oil absorption. Such may be useful food additives. Incertain preferred embodiments, the compounds produced by theintermediates according to the present invention may be co-administeredalong with other compounds typically prescribed for these conditionsaccording to generally accepted medical practice such as other dietarymaintenance medicaments and for diseases related to or impacted by theabsorption of dietary fat. The compounds produced from the intermediatesaccording to the present invention may act in a synergistic fashion withother such medicaments. Such compounds may also allow for reduced dosesof other cholesterol inhibiting, appetite inhibiting and metabolicstimulating medicaments, and the like. Such compounds can be utilized invivo, ordinarily in mammals such as primates, (non-human and humans),sheep, horses, cattle, pigs, dogs, cats, rats and mice, or in vitro.

The starting materials used in above processes are commerciallyavailable from chemical vendors such as Aldrich, Sigma, Lancaster, TCI,and the like, or may be readily synthesized by known procedures, forexample, by using procedures such as indicated above.

Reactions are carried out in standard laboratory glassware and reactionvessels under reaction conditions of standard temperature and pressure,except where otherwise indicated, or is well-known in literatureavailable in the art. Further, the above procedures of the claimedinvention processes my be carried out on a commercial scale by utilizingreactors and standard scale-up equipment available in the art forproducing large amounts of compounds in the commercial environment. Suchequipment and scale-up procedures are well-known to the ordinarypractitioner in the field of commercial chemical production.

During the synthesis of these compounds, amino or acid functional groupsmay be protected by blocking groups to prevent undesired reactions withthe amino group or acid group during certain procedures. Procedures forsuch protection and removal of protecting groups are routine in this artand well-known to the ordinary practitioner in this field.

Four non-limiting exemplary synthesis schemes were shown above, whichare each a preferred embodiment of the invention, comprise the processsteps outlined above which may also include further initial startingsteps such as those set forth in J. Med. Chem., Vol. 15, No. 8 (1972) orfurther processing steps which modify the amino group to comprise adesired functional group such as groups described in the lipaseinhibiting field. Amino coupling reactions are well-known in the art.Moreover, specific steps that are set forth in the preferred embodimentreaction scheme described above. The reaction products are isolated andpurified by conventional methods, typically by solvent extraction into acompatible solvent. Preferred solvents are lower alkane ethers andalcohols; ethyl ether and isopropyl alcohol are preferred for solventextraction or recrystallization procedures. Esters of carboxylic acidside groups may be formed that permit selective separation of the R andS enantiomers by solvent extraction or recrystallization. D-alaninol isthe preferred enantiomer resolving agent, but other resolving agents oranalogous procedures may be used, e.g., tartartic acid derivatives andthe like. The products may be further purified by column chromatographyor other appropriate methods.

Enantiomeric Resolution and Acid Salt Formation

As is clear from the above formulae and the discussion above, by usingthe above reactions racemic chromane acetic acid is obtained which mayoptionally be resolved to produce a racemic mixture enriched in eitherthe R or S enantiomers or completely resolved into a substantially purecomposition of one of the enantiomers. The literature in this fielddescribes examples of conventional processes whereby the enantiomers maybe resolved.

Coupling Reaction of the Hydrochloride Salt Intermediate Compounds

The above compounds produced according to the above invention may beisolated and further reacted to substitute a desired group for one ormore of the hydrogen atoms on an amino group, on a free hydroxyl groupor on a free acyl group by a coupling reaction with the desired group.

Compositions and Formulations

The compounds of this invention may be isolated as the free acid or baseor converted to salts of various inorganic and organic acids and bases.Such salts are within the scope of this invention. Non-toxic andphysiologically compatible salts are particularly useful although otherless desirable salts may have use in the processes of isolation andpurification.

A number of methods are useful for the preparation of the saltsdescribed above and are known to those skilled in the art. For example,reaction of the free acid or free base form of a compound of thestructures recited above with one or more molar equivalents of thedesired acid or base in a solvent or solvent mixture in which the saltis insoluble, or in a solvent like water after which the solvent isremoved by evaporation, distillation or freeze drying. Alternatively,the free acid or base form of the product may be passed over an ionexchange resin to form the desired salt or one salt form of the productmay be converted to another using the same general process.

Diagnostic applications of the compounds of this invention willtypically utilize formulations such as solution or suspension. In themanagement of undesired fat absorption the compounds of this inventionmay be utilized in compositions such as tablets, capsules or elixirs fororal administration, sterile solutions or suspensions, and the like, orincorporated into shaped articles. Subjects in need of treatment(typically mammalian) using the compounds of this invention can beadministered dosages that will provide optimal efficacy. The dose andmethod of administration will vary from subject to subject and bedependent upon such factors as the type of mammal being treated, itssex, weight, diet, concurrent medication, overall clinical condition,the particular compounds employed, the specific use for which thesecompounds are employed, and other factors which those skilled in themedical arts will recognize.

Formulations of the compounds of this invention are prepared for storageor administration by mixing the compound having a desired degree ofpurity with physiologically acceptable carriers, excipients, stabilizersetc., and may be provided in sustained release or timed releaseformulations. Acceptable carriers or diluents for therapeutic use arewell known in the pharmaceutical field, and are described, for example,in Remington's Pharmaceutical Sciences, Mack Publishing Co., (A. R.Gennaro edit. 1985). Such materials are nontoxic to the recipients atthe dosages and concentrations employed, and include buffers such asphosphate, citrate, acetate and other organic acid salts, antioxidantssuch as ascorbic acid, low molecular weight (less than about tenresidues) peptides such as polyarginine, proteins, such as serumalbumin, gelatin, or immunoglobulins, hydrophilic polymers such aspolyvinylpyrrolidinone, amino acids such as glycine, glutamic acid,aspartic acid, or arginine, monosaccharides, disaccharides, and othercarbohydrates including cellulose or its derivatives, glucose, mannoseor dextrins, chelating agents such as EDTA, sugar alcohols such asmannitol or sorbitol, counterions such as sodium and/or nonionicsurfactants such as Tween, Pluronics or polyethyleneglycol.

Dosage formulations of the compounds of this invention to be used fortherapeutic administration must be sterile. Sterility is readilyaccomplished by filtration through sterile membranes such as 0.2 micronmembranes, or by other conventional methods. Formulations typically willbe stored in lyophilized form or as an aqueous solution. The pH of thepreparations of this invention typically will be between 3 and 11, morepreferably from 5 to 9 and most preferably from 7 to 8. It will beunderstood that use of certain of the foregoing excipients, carriers, orstabilizers will result in the formation of cyclic polypeptide salts.While the preferred route of administration is by oral tablets, capsulesor other unit dose mechanisms, such as liquids, other methods ofadministration are also anticipated such as in food stuffs, employing avariety of dosage forms. The compounds of this invention are desirablyincorporated into food articles which may include fats to prevent theirabsorption.

The compounds of this invention may also be coupled with suitablepolymers to enhance their therapeutic effects. Such polymers can includelipophilic polymers, such as polysaccharides and the like.

Therapeutically effective dosages may be determined by either in vitroor in vivo methods. For each particular compound of the presentinvention, individual determinations may be made to determine theoptimal dosage required. The range of therapeutically effective dosageswill naturally be influenced by the route of administration, thetherapeutic objectives, and the condition of the patient. For routes ofadministration, the lipase inhibitor activity, in view of the amount offat consumed, must be individually determined for each inhibitor bymethods well known in pharmacology. Accordingly, it may be necessary forthe therapist to titer the dosage and modify the route of administrationas required to obtain the optimal therapeutic effect. The determinationof effective dosage levels, that is, the dosage levels necessary toachieve the desired result, will be within the ambit of one skilled inthe art. Typically, applications of compound are commenced at lowerdosage levels, with dosage levels being increased until the desiredeffect is achieved.

Typically, about 500 mg to 3 g of a lipase inhibitor compound or mixtureof lipase inhibitor compounds of this invention, as the free acid orbase form or as a pharmaceutically acceptable salt, is compounded with aphysiologically acceptable vehicle, carrier, excipient, binder,preservative, stabilizer, dye, flavor etc., as called for by acceptedpharmaceutical practice. The amount of active ingredient in thesecompositions is such that a suitable dosage in the range indicated isobtained. The addition, one or more other therapeutic ingredients suchas a fat absorbing polysaccharide or fiber, a fat-specific lipaseinhibitor or lipase, as well as other dietary agents may be utilized intherapeutically effective amounts.

Typical adjuvants which may be incorporated into tablets, capsules andthe like are a binder such as acacia, corn starch or gelatin, andexcipient such as microcrystalline cellulose, a disintegrating agentlike corn starch or alginic acid, a lubricant such as magnesiumstearate, a sweetening agent such as sucrose or lactose, or a flavoringagent. When a dosage form is a capsule, in addition to the abovematerials it may also contain a liquid carrier such as water, saline, afatty oil. Other materials of various types may be used as coatings oras modifiers of the physical form of the dosage unit. Sterilecompositions for injection can be formulated according to conventionalpharmaceutical practice. Buffers, preservatives, antioxidants and thelike can be incorporated according to accepted pharmaceutical practice.

In practicing the methods of this invention, the compounds of thisinvention may be used alone or in combination, or in combination withother therapeutic or diagnostic agents. In certain preferredembodiments, the compounds of this inventions may be coadministeredalong with other compounds typically prescribed for these conditionsaccording to generally accepted medical practice, such as

The compounds of this invention can be utilized in vivo, ordinarily inmammals such as non-human primates, humans, sheep, horses, cattle, pigs,dogs, cats, rats and mice, or in vitro.

The following non-limiting examples are provided to better illustratethe present invention.

EXAMPLE 1

10 grams of low viscosity chitosan is dissolved in a 500 milliliterflask equipped with a stirrer thermometer and electrical heater, in amixture of 190 g of dimethylsulfoxide and 10 g of paraformaldehyde, at50° C. At this temperature, after the addition of 0.1 g of finelypowdered sodium hydroxide, a solution of 400 mg of p-chloromethylbenzoic acid methyl ester in 10 g of dimethylsolfoxide is added over aperiod of about 30 minutes. The mixture is stirred for four hours at 50°C. The reaction mixture is cooled to room temperature, then poured intoethanol while the latter is being stirred vigorously. The solid issuction filtered, suspended repeatedly in ethanol until all the solublesubstances are removed to yield a crude product. The crude product isstirred in an aqueous basic 1 N sodium hydroxide ethanol solution, whichis then acidified with HCl until neutral pH for chitosan. The solid iswashed twice with cold ethanol and cold water, and the solid is thendried to yield about 10 grams of ether functionalized chitosan. Analysisindicates that from 1% to 3% of the free hydroxyl groups on the chitosanpolymeric backbone are etherified by the entry of the p-methylbenzoicacid group.

EXAMPLE 2

A colorless power of 3,5-dihydroxy-2-hexyl-hexadecanoic 1,3-lactone (6g, produced as described on pages 11 and 12 of U.S. Pat. No. 4,202,824)is dissolved in 500 mL of THF to which is added Boc-(L)2-amino-4-methylpentanoic acid chloride (3 g, Boc-(L)-Leucine). Thereaction mixture is stirred and heated to reflux until HPLC indicatesthat the esterification is essentially complete. The organic phase isevaporated and the residue purified by chromatography on silica gel withtoluene-ethyl acetate to yield 5-[Boc-(L)2-amido-4-methylvaleryloxy]-2-hexyl-hexadecanoic 1,3-lactone (6 g).

EXAMPLE 3

The BOC group of the product (6 mg) of Example 2 is removed byhydrogenation at room temperature in 120 mL of THF in the presence of10% Pd/C. After hydrogenation is completed, the catalyst is filtered offand the filtrate is evaporated to yield a crude free amino groupproduct, which is taken up in 100 mL of THF. The functionalized chitosanproduct produced in Example 1 is taken up in 200 mL of THF and stirredwhile the crude free amino product is added dropwise at roomtemperature. The mixture is gradually heated to 40° C. with stirringuntil HPLC indicates the formation of the carboxamide linked product.Yielded is 5-[2-{(4-chitosan methyl ether)benzoylamido}-4-methylvaleryloxy]-2-hexyl-hexadecanoic 1,3-lactone(about 15 grams).

EXAMPLE 4

To a 1 liter flask was added 20 g of chitosan that had been dissolved in350 mL of DMF (N,N-dimethylformamide), with stirring and the temperaturewas raised to 50° C. A mixture of 0.2 g of NaOH and 1 g of6-bromohexanoic acid in 20 mL of DMF was added slowly over 30 minuteswith stirring. The reaction mixture was stirred at 50° C. for 4 hours.The reaction mixture was cooled to room temperature and poured into 500mL of ethanol. The solid is suction filtered and washed three times withcold ethanol. The crude precipitate was treated in 1N NaOH ethanolsolution for 3 hours, then the pH was reduced to neutral by the additionof 1N HCl. The solid was washed with cold ethanol and H₂O (4:1 ratio) 3times and dried to provide 19.7 g of functionalized chitosan.

EXAMPLE 6

To 200 mL of THF (tetrahydrofuran) was added 9 g of the functionalizedchitosan from Example 5, with stirring. To this mixture was added 10mmol of HBTU (1H-benzotriazolium-1-[bis,(dimethylamino)methylene]-hexafluorophosphate(1-)-3-oxide) dissolved in10 mL of DMF with stirring over a 10 minute period. TetrahydrostatinL-leucine ester (about 525 mg) dissolved in 100 mL of THF was addeddropwise with stirring. The pH was then adjusted to about 8.5 by theaddition of DIEA (disopropylethylamine) and the mixture was stirred atroom temperature overnight. The reaction mixture was reduced in volumeby evaporated under vacuum to about 50% volume and 500 mL of hexane wasadded. The mixture was filtered and the solid cake was washed with coldhexane three times and then with a cold ethanol/water (3:1) solution 3times. The filter cake was dried under a lyophilizer to yield 9.3 gramsof final product 2S, 3S, 4S [2-{(hexanoic acid modified chitosan6-hexanoylamido}-4-methylvaleryloxy]-2-hexyl-hexadecanoic 1,3-lactone(Compound A).

EXAMPLE 7

To 200 mL of THF was dissolved with stirring 10.65 g of thefunctionalized chitosan from Example 5, above, followed by 2 mmoles ofHBTU. The mixture was stirred together for 15 minutes and then 350 mg of2S, 3S, 4S 2-hexyl-4-hydroxy-hexadecanoic 1,3 lactone that was dissolvedin 30 mL of THF (tetrahydrofuran) was added. The pH was adjusted toabout 8.5 by the addition of DIEA and the mixture was stirred overnight.The reaction mixture was filtered and the solid was washed with coldhexane 3 times and then washed 3 times with a cold ethanol/water (3:1)mixture. The filter cake was dried under a lyophilizer to yield 11.1 gof final product 4-[{(hexanoic acid modified chitosan6-hexanoyloxy}-2-hexyl-hexadecanoic 1,3-lactone (Compound B).

BIOLOGICAL AND OTHER PROPERTIES ASSAY EXAMPLES EXAMPLE 8

Lipase inhibition assays were performed essentially as follows usingeach of Compounds A and B.

A 1 L stock solution of 1N NaOH was made and a 500 mL stock solution of0.025 N NaOH was made by diluting a portion of the stock 1N solution.Also a stock solution of 0.2 N HCl was made. A 100 mL TRIZMA solution(from Aldrich Lipase Assay Kit Cat. No. 800B) was diluted with 100 mL ofdenatured EtOH and 300 mL of water to form a 500 mL TEW solution.Compound A from Example 6 (100 mg) was added to a portion of the 0.2 NHCl stock solution and diluted to a final volume of 300 mL with the sameHCl stock solution to form a compound A stock solution. Compound B fromExample 7 was added to a portion of the 0.2 N HCl stock solution anddiluted to a final volume of 80 mL with the same HCl stock solution toproduce a compound B stock solution. Aldrich Lipase PS Standard (humanlipase 3 mL×3) Aldrich Product No. 8054 was diluted with isotonic salinesolution to a 25 mL volume (Lipase #1 solution). Likewise Aldrich PorkPancreas Lipase [EC 3.1.1.3] Product No. 32313 was diluted to a finalvolume of 25 mL with isotonic saline (Lipase #2 solution). Aldrich SigmaLipase Substrate Standard Cat. Product No. 62314 (3×100, 300 mL) wasobtained to use as the lipid source.

In a 500 mL beaker equipped with a heat source and a magnetic stirrerwas added 100 mL of distilled water, 10 mL of TEW solution, 10 mL ofSigma Lipase Substrate and a 20 mL sample (sample control was 20 mL ofthe stock 0.2 N HCl solution, sample A was 20 mL of the compound A stocksolution, and sample B was 20 mL of the compound B stock solution). ThepH was adjusted to about 8 with 1N NaOH using a pH meter, whose readingwas noted and recorded as a baseline reading after the pH adjustment.The temperature was brought to 37.5° C. and 1 mL of either Lipase #1 orLipase #2 was added and a timer was started for 30 minutes. The mixturewas stirred and the temperature maintained between 35° C. and 37° C. Atthe end of the time period, the mixture was stirred and triturated with0.025 N NaOH. The volume of NaOH solution used to return to the baselinepH reading was noted and recorded. The percent inhibition by the SampleA or Sample B was calculated by subtracting the volume of NaOH used toreturn from baseline pH for either of Sample A or Sample B from theaverage volume of NaOH used to return from baseline pH for the controlsample (three runs), the difference is divided by the average volume ofNaOH used to return to baseline pH for the control sample, and theresult was multiplied by 100% to obtain the percent inhibition of SampleA or Sample B (two runs each).

Each of Sample A and B showed a percent inhibition of about 50% withrespect to the control for each of Lipase #1 and Lipase #2.

EXAMPLE 9

Oil binding assay were performed using each of Compounds A and B usingthe procedures essentially as follows.

Six controls were obtained by adding Star Brand Olive Oil (extra virginlight colored olive oil) to 4 or 7 mL sample bottles, which werephotographed at a distance of 10 inches by using an IZONE POLAROIDcamera as follows. Control 1 was obtained by adding 3 mL of olive oil toa 7 mL bottle, which showed the clear but light reflective oil. Control2 was obtained by adding 3 mL of olive oil to a 7 mL bottle and adding10 drops of McCormick Schilling Red Food Coloring (RFC), which showedthe oil insoluble food color at the bottom of the bottle and floating ontop of the red food coloring is the 3 mL of light reflective olive oil.Control 3 was obtained by adding 3 mL of olive oil to a 7 mL bottle andadding 3 mL of water followed by 5 drops RFC, which showed of the clearseparation of the red aqueous layer on the bottom of the bottle andfloating on top was the light reflective olive oil. Control 4 wasobtained by adding 1.5 g of olive oil to 1 g of chitosan (Natural MaxBrand, greater than 90% deacylated chitin) and the two were mixed with astirrer, followed by the addition of 4 mL of water and 5 drops of RFC,which showed the oil tightly bound to the chitosan in the bottom of thebottle, upon which was floating the aqueous red food color layer (aclean red meniscus with substantially no floating oil was observed).Control 5 was obtained by adding 1.5 g of olive oil to 1 g of cellulose(Avicel) and the two were mixed with a stirrer, followed by the additionof 4 mL of water and 5 drops of RFC, which showed some oil bound in thebottom to the cellulose, upon which was floating the aqueous red foodcolor layer, further upon which was floating a clear layer of oil, about¾ mL (a clear floating oily layer meniscus was observed to show thatcellulose does not tightly bind an excess of its weight in oil. Control6 was obtained by adding 8 g of olive oil to 1 g of chitosan and the twowere mixed together with a stirrer, followed by the addition of 1 mL ofwater and 5 drops of RFC, which shows an hour-glass shape of oil boundby chitosan surrounded in the middle of the bottle at the narrow pointwith the aqueous red food color solution (chitosan binds oil andsubstantially excludes water from the bound mixture).

For comparison with Control 4 (oil/chitosan 1.5/1 ratio) each ofCompounds A and B were mixed with oil in the same ratio(oil/compound1.5/1 ratio, green food coloring was added to the aqueous portion of thecompound A sample bottle and blue food coloring was added to the aqueousportion of the compound B sample bottle). The same results occurred witheach of Compounds A and B as for the chitosan Control 4, in that the oilis bound tightly at the bottom of the bottle and there is substantiallyno floating oil, i.e., the meniscus for each is a clean green and bluemeniscus. However, Compound B appeared to perhaps bind the oil moretightly than either chitosan or compound A.

For comparison with Control 6 (oil/chitosan 8:1 ratio and 1 mL ofaqueous solution with food coloring), compound B was added to 8 timesits weight of oil and stirred to a uniform consistency. The 1 mL ofwater was added and 5 drops of red food coloring were added. Uponmixing, the oil and compound B swelled to form a grainy gel-likeconsistency and uniformly absorbed the 1 mL of aqueous food coloringsolution to form a homogenous layer which was present even after 24hours. This shows that compound B has the ability to bind oil and thenabsorb at least its weight in water to form grainy gel-like homogeneousmixture, and continues to tightly bind the oil while being hydrated withwater.

In view of the above description it is believed that one of ordinaryskill can practice the invention. The examples given above arenon-limiting in that one of ordinary skill in view of the above willreadily envision other permutations and variations on the inventionwithout departing from the principal concepts. Such permutations andvariations are also within the scope of the present invention.

What is claimed is:
 1. A novel oxetanone derivative of the formula:

wherein: t is an integer from 0 to 1 X-L-Q is an ether or amino linkagewherein: X of the ether or amino is a linking group, L is —O— or —NH—,and Q of the ether or amino linkage is a polysaccharide of a sufficientmolecular weight or property that such polysaccharide is not absorbed bythe digestive system of a mammal such as a dog, cat, non-human primateor a human primate; R is a member selected from the group consisting of:a straight or branched chained C₁₋₁₇-alkyl group which is saturated oroptionally substituted by up to eight double or triple bonds; a straightor branched chained C₁₋₁₇-alkyl group which is saturated or optionallysubstituted by one or more members selected from the group consisting ofan oxygen atom, a sulfur atom, a sulfonyl group or a sulfinyl group; astraight or branched chained C₁₋₁₇-alkyl group which is saturated oroptionally substituted by up to eight double or triple bonds and issubstituted in a position other than alpha to an unsaturated carbon atomby one or more members selected from the group consisting of an oxygenatom, a sulfur atom, a sulfonyl group or a sulfinyl group atoms; phenylsubstituted by 0-4 members selected from the group consisting of—C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl, —C₁₋₆-alkyl-OHand —C₁₋₆-alkyl-SH; benzyl substituted by 0-4 members selected from thegroup consisting of —C₁₋₆-alkyloxy-C₁₋₆-alkyl,—C₁₋₆-alkylthio-C₁₋₆-alkyl, —C₁₋₆-alkyl-OH and —C₁₋₆-alkyl-SH;biphenylene substituted by 0-6 members selected from the groupconsisting of —C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl,—C₁₋₆-alkyl-OH and —C-₁₋₆-alkyl-SH; phenoxyphenylene substituted by 0-6members selected from the group consisting of —C₁₋₆-alkyloxy-C₁₋₆-alkyl,—C₁₋₆-alkylthio-C₁₋₆-alkyl, —C₁₋₆-alkyl-OH and —C₁₋₆-alkyl-SH;phenylthiophenylene substituted by 0-6 members selected from the groupconsisting of —C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl,—C₁₋₆-alkyl-OH and —C₁₋₆-alkyl-SH; and phenyl-C₁₋₆-alkyl-phenyl wherein0-6 hydrogen atoms on one or more of the phenyl ring and —C₁₋₆-alkyl-group is/are replaced independently by a member selected from the groupconsisting of—C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl,—C₁₋₆-alkyl-OH and —C₁₋₆-alkyl-SH; R¹ is a member selected from thegroup consisting of: Hydrogen, Ar, Ar-C₁₋₅-alkyl and C₁₋₁₀-alkylsubstituted by 0-3 members independently selected from the groupconsisting of an oxygen atom, a sulfur atom, a sulfinyl group, asulfonyl group, a-N(—R⁴)— group, a —C(═O)—N(—R⁴)— group, and a—N(—R⁴)—C(═O)— group, wherein 0-3 carbon atoms of the C₁₋₁₀-alkyl groupcan be substituted independently by a member selected from the groupconsisting of a hydroxy group, thiol group, C₁₋₁₀-alkoxy group, aC₁₋₁₀-alkylthio group, a —N(—R⁵,—R⁶) group, a —C(═O)—N(—R⁷, —R⁸) group,and a —N(—R⁹)—C(═O)—R¹⁰ group; R² is a member selected from the groupconsisting of: hydrogen and C₁₋₆-alkyl, or R² taken with R¹ forms a 4-6membered saturated ring containing 0-4 nitrogen atoms wherein the ringmay be substituted by 0-4 R¹¹ groups; R³ is a member selected from thegroup consisting of: a straight or branched chained C₁₋₁₇-alkyl groupwhich is saturated or optionally substituted by up to eight double ortriple bonds; a straight or branched chained C₁₋₁₇-alkyl group which issaturated or optionally substituted by one or more members selected fromthe group consisting of an oxygen atom, a sulfur atom, a sulfonyl groupor a sulfinyl group; a straight or branched chained C₁₋₁₇-alkyl groupwhich is saturated or optionally substituted by up to eight double ortriple bonds and is substituted in a position other than alpha to anunsaturated carbon atom by one or more members selected from the groupconsisting of an oxygen atom, a sulfur atom, a sulfonyl group or asulfinyl group atoms; phenyl substituted by 0-4 members selected fromthe group consisting of —C₁₋₆-alkyloxy-C₁₋₆-alkyl,—C₁₋₆-alkylthio-C₁₋₆-alkyl, —C₁₋₆-alkyl-OH and —C₁₋₆-alkyl-SH; benzylsubstituted by 0-4 members selected from the group consisting of—C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl, —C₁₋₆-alkyl-OHand —C₁₋₆-alkyl-SH; biphenylene substituted by 0-6 members selected fromthe group consisting of —C₁₋₆-alkyloxy-C₁₋₆-alkyl,—C₁₋₆-alkylthio-C₁₋₆-alkyl, —C₁₋₆-alkyl-OH and —C₁₋₆-alkyl-SH;phenoxyphenylene substituted by 0-6 members selected from the groupconsisting of —C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl,—C₁₋₆-alkyl-OH and —C₁₋₆-alkyl-SH; phenylthiophenylene substituted by0-6 members selected from the group consisting of—C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl, —C₁₋₆-alkyl-OHand —C₁₋₆-alkyl-SH; and phenyl-C₁₋₆-alkyl-phenyl wherein 0-6 hydrogenatoms on one or more of the phenyl ring and —C₁₋₆-alkyl- group is/arereplaced independently by a member selected from the group consisting of—C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl, —C₁₋₆-alkyl-OHand —C₁₋₆-alkyl-SH; R⁴-R¹⁰ are each independently a member selected fromthe group consisting of: hydrogen and C₁₋₆-alkyl; n is an integer of0-3; or a pharmaceutically acceptable isomer, and salt thereof.
 2. Acompound according to claim 1, wherein L is —NH—, or a pharmaceuticallyacceptable isomer and salt thereof.
 3. A compound according to claim 1,wherein X is the group —(C(═O))₀₋₁—X_(a)—, wherein X_(a) is a memberselected from the group consisting of: a straight or branched chaineddivalent C₁₋₁₇-alkylene group which is saturated or optionallysubstituted by up to eight double or triple bonds; a straight orbranched chained divalent C₁₋₁₇-alkylene group which is saturated oroptionally substituted by one or more members selected from the groupconsisting of: an oxygen atom, a sulfur atom, a sulfonyl group, asulfinyl group, a substituted or unsubstituted 6-10 member monocyclic orbicyclic aryl or heteroaryl group having from 1-4 ring hetero atomsselected from the group consisting of O, N, S, a —NH— group, wherein thehydrogen atom may be replaced with a C₁₋₁₀ alkyl group a —C(═O)— group,a —NH—C(═O)— group, wherein the hydrogen atom may be replaced with aC₁₋₁₀ alkyl group and a —C(═O)—NH— group, wherein the hydrogen atom maybe replaced with a C₁₋₁₀ alkyl group a straight or branched chaineddivalent C₁₋₁₇-alkylene group which is saturated or optionallysubstituted by up to eight double or triple bonds and is substituted ina position other than alpha to an unsaturated carbon atom by one or moremembers selected from the group consisting optionally substituted by oneor more members selected from the group consisting of: an oxygen atom, asulfur atom, a sulfonyl group, a sulfinyl group, a substituted orunsubstituted 6-10 member monocyclic or bicyclic aryl or heteroarylgroup having from 1-4 ring hetero atoms selected from the groupconsisting of O, N, S, a —NH— group, wherein the hydrogen atom may bereplaced with a C₁₋₁₀ alkyl group a —C(═O)— group, a —NH—C(═O)— group,wherein the hydrogen atom may be replaced with a C₁₋₁₀ alkyl group and a—C(═O)—NH— group, wherein the hydrogen atom may be replaced with a C₁₋₁₀alkyl group divalent phenylene or divalent naphthylene substituted onthe ring structure by 0-4 members selected from the group consisting of—C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl, —C₁₋₆-alkyl-OHand —C₁₋₆-alkyl-SH; divalent biphenylene substituted by 0-6 membersselected from the group consisting of —C₁₋₆-alkyloxy-C₁₋₆-alkyl,—C₁₋₆-alkylthio-C₁₋₆-alkyl, —C₁₋₆-alkyl-OH and —C₁₋₆-alkyl-SH;phenoxyphenylene substituted by 0-6 members selected from the groupconsisting of —C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl,—C₁₋₆-alkyl-OH and —C₁₋₆-alkyl-SH; divalent phenylthiophenylenesubstituted by 0-6 members selected from the group consisting of—C₁₋₆-alkyloxy-C₁₋₆-alkyl, —C₁₋₆-alkylthio-C₁₋₆-alkyl, —C₁₋₆-alkyl-OHand —C₁₋₆-alkyl-SH; and or a pharmaceutically acceptable isomer and saltthereof.
 4. The compound of claim 3, wherein R is —(CH₂)₃₋₆—CH₃ and R³is a member selected from the group consisting of —(CH₂)₈₋₁₄—CH₃ and—CH₂—CH═CH—CH₂—CH═CH—(CH₂)₂₋₈—CH₃, or a pharmaceutically acceptableisomer and salt thereof.
 5. The compound of claim 3, wherein R is—(CH₂)₅—CH₃ and R³ is a member selected from the group consisting of—(CH₂)₁₀—CH₃ and —CH₂—CH═CH—CH₂—CH═CH—(CH₂)₄—CH₃, or a pharmaceuticallyacceptable isomer and salt thereof.
 6. The compound of claim 3, whereinn is zero to provide compounds of the formula:

wherein: X, L, t, Q, R, R¹, R² and R³ are defined as in claim 2, or anisomer and salt thereof.
 7. The compound of claim 6, wherein R is—(CH₂)₃₋₆—CH₃ and R³ is a member selected from the group consisting of—(CH₂)₈₋₁₄—CH₃ and —CH₂—CH═CH—CH₂—CH═CH—(CH₂)₂₋₈—CH₃, or an isomer andsalt thereof.
 8. The compound of claim 6, wherein R is —(CH₂)₅—CH₃ andR³ is a member selected from the group consisting of —(CH₂)₁₀—CH₃ and—CH₂—CH═CH—CH₂—CH═CH—(CH₂)₄—CH₃, or an isomer and salt thereof.
 9. Thecompound of claim 6, wherein t is 0, or an isomer and salt thereof. 10.The compound of claim 3, wherein t is 0 or 1 and X is a member selectedfrom the group consisting of:

wherein R^(1a) is independently defined the same as defined for R¹,R^(2a) is independently defined the same as for R², m is a integer from0 to 10, and wherein z is an integer from 1 to 20, or a pharmaceuticallyacceptable isomer and salt thereof.
 11. The compound of claim 10,wherein X is a member selected from the group consisting of:

and wherein z is a integer from 0 to 10, or a pharmaceuticallyacceptable isomer and salt thereof.
 12. The compound of claim 10,wherein X is a member selected from the group consisting of:

and wherein z is a integer from 0 to 18, or a pharmaceuticallyacceptable isomer and salt thereof.
 13. The compound of claim 10,wherein X is a member selected from the group consisting of:

and wherein z is a integer 6-12, or a pharmaceutically acceptable isomerand salt thereof.
 14. The compound of claim 10, wherein X is a memberselected from the group consisting of:

and wherein z is a integer 6-12, or a pharmaceutically acceptable isomerand salt thereof.
 15. The compound of claim 2, wherein the Q group is achitosan compound modified by attaching a sufficient number of organicacyl groups to hydroxyl groups, amino groups or amino and hydroxylgroups, to cause the modified chitosan to absorb or associate bothlipids and water and to form a substantially homogenous gel with lipidsand water.
 16. A method for producing a compound of claim 1, comprisingreacting a compound of the formula:

with a compound of the formula

wherein t is 0 or 1 and Y is a leaving group for an etherification oresterification reaction with the hydroxy group to produce a compound ofthe formula:

or a salt thereof.
 17. A pharmaceutical composition comprising at leastone pharmaceutically acceptable carrier excipient and an amount of atleast one compound according to claim 1 in a therapeutically effectiveamount with respect to limiting or preventing the absorption of somedietary fat.
 18. A pharmaceutical composition according to claim 17,further comprising a therapeutically effective amount of an oilabsorbing effective amount of polysaccharide such as chitosan.
 19. Amethod of using a compound according to claim 1 as a therapeutic agentfor disease states in a mammal having at least one disorder that is dueto undesired absorption of dietary fat or for reducing the effectivecaloric intake of a mammal who consumes dietary fat.
 20. A methodaccording to claim 18 as part of a treatment method for managing orcontrolling undesired weight gain or obesity.
 21. A method of using acomposition according to claim 16 as a therapeutic agent for diseasestates in a mammal having at least one disorder that is due to undesiredabsorption of dietary fat or for reducing the effective caloric intakeof a mammal who consumes dietary fat.
 22. A compound according to claim2, wherein organic acyl groups are present on the modified chitosanchain of the Q group in a molar ratio from 1 to 8 times the number ofthe molar ratio of esterified lipase inhibitor alcohol groups.
 23. Acompound according to claim 2, wherein the hydroxyl groups, amino groupsor both hydroxyl and amino groups of Q are modified by the attachment ofa sufficient number of organic acyl groups to cause Q to absorb orassociate with both lipids and water and to form a substantiallyhomogeneous gel with lipids and water.